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Gomez-Pinedo U, Matías-Guiu JA, Torre-Fuentes L, Montero-Escribano P, Hernández-Lorenzo L, Pytel V, Maietta P, Alvarez S, Sanclemente-Alamán I, Moreno-Jimenez L, Ojeda-Hernandez D, Villar-Gómez N, Benito-Martin MS, Selma-Calvo B, Vidorreta-Ballesteros L, Madrid R, Matías-Guiu J. Variant rs4149584 (R92Q) of the TNFRSF1A gene in patients with familial multiple sclerosis. Neurologia 2025; 40:10-21. [PMID: 35963536 DOI: 10.1016/j.nrleng.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION Genomic studies have identified numerous genetic variants associated with susceptibility to multiple sclerosis (MS); however, each one explains only a small percentage of the risk of developing the disease. These variants are located in genes involved in specific pathways, which supports the hypothesis that the risk of developing MS may be linked to alterations in these pathways, rather than in specific genes. We analyzed the role of the TNFRSF1A gene, which encodes one of the TNF-α receptors involved in a signaling pathway previously linked to autoimmune disease. METHODS We included 138 individuals from 23 families including at least 2 members with MS, and analyzed the presence of exonic variants of TNFRSF1A through whole-exome sequencing. We also conducted a functional study to analyze the pathogenic mechanism of variant rs4149584 (-g.6442643C > G, NM_001065.4:c.362 G > A, R92Q) by plasmid transfection into human oligodendroglioma (HOG) cells, which behave like oligodendrocyte lineage cells; protein labeling was used to locate the protein within cells. We also analyzed the ability of transfected HOG cells to proliferate and differentiate into oligodendrocytes. RESULTS Variant rs4149584 was found in 2 patients with MS (3.85%), one patient with another autoimmune disease (7.6%), and in 5 unaffected individuals (7.46%). The 2 patients with MS and variant rs4149584 were homozygous carriers and belonged to the same family, whereas the remaining individuals presented the variant in heterozygosis. The study of HOG cells transfected with the mutation showed that the protein does not reach the cell membrane, but rather accumulates in the cytoplasm, particularly in the endoplasmic reticulum and near the nucleus; this suggests that, in the cells presenting the mutation, TNFRSF1 does not act as a transmembrane protein, which may alter its signaling pathway. The study of cell proliferation and differentiation found that transfected cells continue to be able to differentiate into oligodendrocytes and are probably still capable of producing myelin, although they present a lower rate of proliferation than wild-type cells. CONCLUSIONS Variant rs4149584 is associated with risk of developing MS. We analyzed its functional role in oligodendrocyte lineage cells and found an association with MS in homozygous carriers. However, the associated molecular alterations do not influence the differentiation into oligodendrocytes; we were therefore unable to confirm whether this variant alone is pathogenic in MS, at least in heterozygosis.
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Affiliation(s)
- U Gomez-Pinedo
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain.
| | - J A Matías-Guiu
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - L Torre-Fuentes
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - P Montero-Escribano
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - L Hernández-Lorenzo
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - V Pytel
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain; Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | | | | | - I Sanclemente-Alamán
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - L Moreno-Jimenez
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - D Ojeda-Hernandez
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - N Villar-Gómez
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - M S Benito-Martin
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - B Selma-Calvo
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - L Vidorreta-Ballesteros
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | | | - J Matías-Guiu
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain; Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
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Cao Z, Zhu Y, Li Y, Yuan Z, Han B, Guo Y. The mechanical regulatory role of ATP13a3 in osteogenic differentiation of pre-osteoblasts. Adv Med Sci 2024; 69:339-348. [PMID: 39004219 DOI: 10.1016/j.advms.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/24/2024] [Accepted: 07/06/2024] [Indexed: 07/16/2024]
Abstract
PURPOSE The process of osteogenic differentiation hinges upon the pivotal role of mechanical signals. Previous studies found that mechanical tensile strain of 2500 microstrain (με) at a frequency of 0.5 Hz promoted osteogenesis in vitro. However, the mechanism of the mechanical strain influencing osteogenesis at the cellular and molecular levels are not yet fully understood. This study aimed to explore the mechanism of mechanical strain on osteogenic differentiation of MC3T3-E1 cells. MATERIALS AND METHODS Proteomics analysis was conducted to explore the mechanical strain that significantly impacted the protein expression. Bioinformatics identified important mechanosensitive proteins and the expression of genes was investigated using real-time PCR. The dual-luciferase assay revealed the relationship between the miRNA and its target gene. Overexpression and downexpression of the gene, to explore its role in mechanically induced osteogenic differentiation and transcriptomics, revealed further mechanisms in this process. RESULTS Proteomics and bioinformatics identified an important mechanosensitive lowexpression protein ATP13A3, and the expression of Atp13a3 gene was also reduced. The dual-luciferase assay revealed that microRNA-3070-3p (miR-3070-3p) targeted the Atp13a3 gene. Furthermore, the downexpression of Atp13a3 promoted the expression levels of osteogenic differentiation-related genes and proteins, and this process was probably mediated by the tumor necrosis factor (TNF) signaling pathway. CONCLUSION Atp13a3 responded to mechanical tensile strain to regulate osteogenic differentiation, and the TNF signaling pathway regulated by Atp13a3 was probably involved in this process. These novel insights suggested that Atp13a3 was probably a potential osteogenesis and bone formation regulator.
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Affiliation(s)
- Zhen Cao
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China; Department of Histology & Embryology, College of Basic Medical Sciences, Dalian Medical University, Liaoning, China
| | - Yingwen Zhu
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China
| | - Yanan Li
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China
| | - Zijian Yuan
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China
| | - Biao Han
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China.
| | - Yong Guo
- Department of Biomedical Engineering, School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, China; Key Laboratory of Biochemistry and Molecular Biology (Guilin Medical University), Education Department of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China.
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Cheng Y, Liu Y, Xu D, Zhang D, Yang Y, Miao Y, He S, Xu Q, Li E. An engineered TNFR1-selective human lymphotoxin-alpha mutant delivered by an oncolytic adenovirus for tumor immunotherapy. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167122. [PMID: 38492783 DOI: 10.1016/j.bbadis.2024.167122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 02/25/2024] [Accepted: 03/10/2024] [Indexed: 03/18/2024]
Abstract
Lymphotoxin α (LTα) is a soluble factor produced by activated lymphocytes which is cytotoxic to tumor cells. Although a promising candidate in cancer therapy, the application of recombinant LTα has been limited by its instability and toxicity by systemic administration. Secreted LTα interacts with several distinct receptors for its biological activities. Here, we report a TNFR1-selective human LTα mutant (LTα Q107E) with potent antitumor activity. Recombinant LTα Q107E with N-terminal 23 and 27 aa deletion (named LTα Q1 and Q2, respectively) showed selectivity to TNFR1 in both binding and NF-κB pathway activation assays. To test the therapeutic potential, we constructed an oncolytic adenovirus (oAd) harboring LTα Q107E Q2 mutant (named oAdQ2) and assessed the antitumor effect in mouse xenograft models. Intratumoral delivery of oAdQ2 inhibited tumor growth. In addition, oAdQ2 treatment enhanced T cell and IFNγ-positive CD8 T lymphocyte infiltration in a human PBMC reconstituted-SCID mouse xenograft model. This study provides evidence that reengineering of bioactive cytokines with tissue or cell specific properties may potentiate their therapeutic potential of cytokines with multiple receptors.
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Affiliation(s)
- Yan Cheng
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China
| | - Yu Liu
- Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China
| | - Dongge Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China
| | - Dan Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China
| | - Yang Yang
- Shanghai Baoyuan Pharmaceutical Co., Ltd, Shanghai, China
| | - Yuqing Miao
- The Affiliated Yancheng First People's Hospital, Medical School, Nanjing University, Yancheng, China
| | - Susu He
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China; The Affiliated Yancheng First People's Hospital, Medical School, Nanjing University, Yancheng, China
| | - Qing Xu
- Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China; Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China.
| | - Erguang Li
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China; Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China.
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Nagai H, Mukozu T, Matsui T, Mohri K, Nagumo H, Yoshimine N, Kobayashi K, Ogino Y, Daido Y, Wakui N, Momiyama K, Matsuda T, Igarashi Y, Higai K. Remaining Issues Related to Serum Cytokines in Patients with Unresectable Hepatocellular Carcinoma Treated by Atezolizumab plus Bevacizumab Combination Treatment. Oncology 2024; 102:828-840. [PMID: 38402871 DOI: 10.1159/000537965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 02/15/2024] [Indexed: 02/27/2024]
Abstract
INTRODUCTION Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. METHODS We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. RESULTS In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. CONCLUSION These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC.
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Affiliation(s)
- Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kunihide Mohri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Hideki Nagumo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Naoyuki Yoshimine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kojiro Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yu Ogino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yasuko Daido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koichi Momiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koji Higai
- Department of Medical Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
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Vugler A, O’Connell J, Nguyen MA, Weitz D, Leeuw T, Hickford E, Verbitsky A, Ying X, Rehberg M, Carrington B, Merriman M, Moss A, Nicholas JM, Stanley P, Wright S, Bourne T, Foricher Y, Zhu Z, Brookings D, Horsley H, Heer J, Schio L, Herrmann M, Rao S, Kohlmann M, Florian P. An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis. Front Pharmacol 2022; 13:1037983. [PMID: 36467083 PMCID: PMC9709720 DOI: 10.3389/fphar.2022.1037983] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/21/2022] [Indexed: 07/30/2023] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.
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Affiliation(s)
- Alexander Vugler
- Immunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - James O’Connell
- Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Mai Anh Nguyen
- Sanofi R&D, TMED Pharmacokinetics Dynamics and Metabolism, Frankfurt am Main, Germany
| | - Dietmar Weitz
- Sanofi R&D, Drug Metabolism and Pharmacokinetics, Frankfurt am Main, Germany
| | - Thomas Leeuw
- Sanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, Germany
| | - Elizabeth Hickford
- Development Science, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | | | - Xiaoyou Ying
- Sanofi R&D, Translation In vivo Models, Cambridge, MA, United States
| | - Markus Rehberg
- Sanofi R&D, Translational Disease Modelling, Frankfurt am Main, Germany
| | - Bruce Carrington
- Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Mark Merriman
- Immunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Andrew Moss
- Translational Medicine Immunology, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Jean-Marie Nicholas
- Development Science, Drug Metabolism and Pharmacokinetics, UCB Pharma, Braine-I’Alleud, Belgium
| | - Phil Stanley
- Immunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Sara Wright
- Early PV Missions, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Tim Bourne
- Milvuswood Consultancy, Penn, United Kingdom
| | - Yann Foricher
- Sanofi R&D, Integrated Drug Discovery, Vitry-sur-Seine, France
| | - Zhaoning Zhu
- Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Daniel Brookings
- Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Helen Horsley
- Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Jag Heer
- Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom
| | - Laurent Schio
- Sanofi R&D, Integrated Drug Discovery, Vitry-sur-Seine, France
| | - Matthias Herrmann
- Sanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, Germany
| | - Srinivas Rao
- Sanofi R&D, Translation In vivo Models, Cambridge, MA, United States
| | - Markus Kohlmann
- Sanofi R&D, Early Clinical Development, Therapeutic Area Immunology and Inflammation, Frankfurt am Main, Germany
| | - Peter Florian
- Sanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, Germany
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Wang X, Yang C, Körner H, Ge C. Tumor Necrosis Factor: What Is in a Name? Cancers (Basel) 2022; 14:5270. [PMID: 36358688 PMCID: PMC9656125 DOI: 10.3390/cancers14215270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 12/18/2024] Open
Abstract
Tumor Necrosis Factor was one of the first cytokines described in the literature as a soluble mediator of cytotoxicity to tumors. Over the years, more extensive research that tried to employ Tumor Necrosis Factor in cancer treatments showed nevertheless that it mainly functioned as a proinflammatory cytokine. However, this did not stop the search for the holy grail of cancer research: A cytokine that could act as a one-stop treatment for solid tumors and lymphomas. This review will summarize the long experimental history of Tumor Necrosis Factor that caused the initial observations of a tumor necrotizing cytokine that could serve as a potential cancer treatment and discuss the current state of research into this side of the activities of Tumor Necrosis Factor.
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Affiliation(s)
- Xinming Wang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Chunlan Yang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Heinrich Körner
- Menzies Institute for Medical Research, Liverpool Street, Hobart, TAS 7000, Australia
| | - Chaoliang Ge
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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Williams PT. Quantile-Specific Heritability of Inflammatory and Oxidative Stress Biomarkers Linked to Cardiovascular Disease. J Inflamm Res 2022; 15:85-103. [PMID: 35023945 PMCID: PMC8743501 DOI: 10.2147/jir.s347402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/16/2021] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Heritability (h2 , the proportion of the phenotypic variance attributable to additive genetic effects) is traditionally assumed to be constant throughout the distribution of the phenotype. However, the heritabilities of circulating C-reactive protein, interleukin-6, plasminogen activator inhibitor type-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) concentrations depend upon whether the phenotype is high or low relative to their distributions (quantile-dependent expressivity), which may account for apparent gene-environment interactions. Whether the heritabilities of other inflammatory biomarkers linked to cardiovascular disease are quantile-dependent remain to be determined. PATIENTS AND METHODS Quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted phenotypes of families surveyed as part of the Framingham Heart Study. Quantile-specific heritabilities were calculated as: h2 =2βOP/(1+rspouse) and h2 ={(1+8rspouseβFS)0.5-1}/(2rspouse). RESULTS Heritability (h2 ± SE) of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass concentrations increased from 0.11 ± 0.03 at the 10th percentile, 0.08 ± 0.03 at the 25th, 0.12 ± 0.03 at the 50th, 0.20 ± 0.04 at the 75th, and 0.26 ± 0.06 at the 90th percentile, or 0.0023 ± 0.0006 per each one-percent increase in the phenotype distribution (Plinear trend= 0.0004). Similarly, h2 increased 0.0029 ± 0.0011 (Plinear trend= 0.01) for sP-selectin, 0.0032 ± 0.0009 (Plinear trend= 0.0001) for soluble intercellular adhesion molecule 1 (sICAM-1), and 0.0026 ± 0.0006 for tumor necrosis factor receptor 2 (TNFR2) (Plinear trend= 5.0 × 10-6) per each one-percent increase in their distributions when estimated from βOP. Osteoprotegerin and soluble ST2 heritability also increased significantly with increasing percentiles of their distributions when estimated from βFS. Lp-PLA2 activity, CD40 ligand, TNFα, interleukin-18, and myeloperoxidase heritability showed no significant quantile-dependence. CONCLUSION The heritabilities of circulating Lp-PLA2-mass, sP-selectin, sICAM-1, TNFR2, osteoprotegerin and soluble ST2 concentrations are quantile-dependent, which may contribute to purported genetic modulations of: 1) sP-selectin's relationships to venous thrombosis, pulmonary hypertension, type 2 diabetes and atorvastatin treatment; 2) sICAM-I's relationships to brain abscess and atorvastatin treatment; and 3) Lp-PLA2's relationships to myocardial infarction and preeclampsia.
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Affiliation(s)
- Paul T Williams
- Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
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Yang Y, Islam MS, Hu Y, Chen X. TNFR2: Role in Cancer Immunology and Immunotherapy. Immunotargets Ther 2021; 10:103-122. [PMID: 33907692 PMCID: PMC8071081 DOI: 10.2147/itt.s255224] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/16/2021] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4+Foxp3+ regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion. There is compelling evidence that tumor necrosis factor (TNF) receptor type II (TNFR2) plays a decisive role in the activation and expansion of Tregs and other types of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs). Furthermore, TNFR2 is also expressed by some tumor cells. Emerging experimental evidence indicates that TNFR2 may be a therapeutic target to enhance naturally occurring or immunotherapeutic-triggered anti-tumor immune responses. In this article, we discuss recent advances in the understanding of the mechanistic basis underlying the Treg-boosting effect of TNFR2. The role of TNFR2-expressing highly suppressive Tregs in tumor immune evasion and their possible contribution to the non-responsiveness to checkpoint treatment are analyzed. Moreover, the role of TNFR2 expression on tumor cells and the impact of TNFR2 signaling on other types of cells that shape the immunological landscape in the tumor microenvironment, such as MDSCs, MSCs, ECs, EPCs, CD8+ CTLs, and NK cells, are also discussed. The reports revealing the effect of TNFR2-targeting pharmacological agents in the experimental cancer immunotherapy are summarized. We also discuss the potential opportunities and challenges for TNFR2-targeting immunotherapy.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Md Sahidul Islam
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
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Etanercept as a TNF-alpha inhibitor depresses experimental retinal neovascularization. Graefes Arch Clin Exp Ophthalmol 2020; 259:661-671. [PMID: 33043386 DOI: 10.1007/s00417-020-04956-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/07/2020] [Accepted: 10/01/2020] [Indexed: 01/06/2023] Open
Abstract
PURPOSE The formation of retinal neovascularization (RNV) is the primary pathological process underlying retinopathy of prematurity (ROP). Previous studies have shown that inflammatory factors are related to the formation of RNV. Tumor necrosis factor-α (TNF-α), as an important factor in the inflammatory response, is involved in the regulation of RNV formation. However, the mechanism through which TNF-α inhibition reduces RNV formation is not fully clarified. Therefore, the purpose of this study was to explore the effect of etanercept, an inhibitor of TNF-α, on RNV, and its possible mechanism. METHODS In vivo, an oxygen-induced retinopathy (OIR) mouse model was used to determine the effect of etanercept on the formation of RNV by performing immunostaining. The effect of etanercept on tumor necrosis factor receptor-associated factor 2 (TRAF2), pro-angiogenic-related factors, and pro/anti-inflammatory factors in OIR mice was assessed by real-time PCR and Western blotting. In vitro, the effect of etanercept on TNF-α-induced human retinal microvascular endothelial cell tube formation was evaluated by tube formation assays, and the potential mechanism of etanercept was explored by Western blotting. RESULTS In vivo, etanercept reduced the area of RNV and decreased the expression of TRAF2 in the OIR mouse model. Etanercept also suppressed the expression of several pro-angiogenic factors and regulated the pro/anti-inflammatory factors. In vitro, etanercept reduced endothelial cell tube formation by inhibiting activation of the NF-κB signaling pathway. CONCLUSION Etanercept can regulate pro/anti-inflammatory factors and reduce the expression of pro-angiogenic factors by inhibiting NF-κB phosphorylation, thereby reducing RNV formation.
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10
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Cui ZW, Kong LL, Zhao F, Tan AP, Deng YT, Jiang L. Two types of TNF-α and their receptors in snakehead (Channa argus): Functions in antibacterial innate immunity. FISH & SHELLFISH IMMUNOLOGY 2020; 104:470-477. [PMID: 32585357 DOI: 10.1016/j.fsi.2020.05.059] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/15/2020] [Accepted: 05/23/2020] [Indexed: 06/11/2023]
Abstract
Tumor necrosis factor-α (TNF-α) is a pluripotent mediator of pro-inflammatory and antimicrobial defense mechanisms and a regulator of lymphoid organ development. Although two types of TNF-α have been identified in several teleost species, their functions in pathogen infection remain largely unexplored, especially in pathogen clearance. Herein, we cloned and characterized two types of TNF-α, termed shTNF-α1 and shTNF-α2, and their receptors, shTNFR1 and shTNFR2, from snakehead (Channa argus). These genes were constitutively expressed in all tested tissues, and were induced by Aeromonas schubertii and Nocardia seriolae in head kidney and spleen in vivo, and by lipoteichoic acid (LTA), lipopolysaccharides (LPS), and Polyinosinic-polycytidylic acid [Poly (I:C)] in head kidney leukocytes (HKLs) in vitro. Moreover, recombinant shTNF-α1 and shTNF-α2 upregulated the expression of endogenous shTNF-α1, shTNF-α2, shTNFR1, and shTNFR2, and enhanced intracellular bactericidal activity, with shTNF-α1 having a greater effect than shTNF-α2. These findings suggest important roles of fish TNFα1, TNFα2, and their receptors in bacterial infection and pathogen clearance, and provide a new insight into their function in antibacterial innate immunity.
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Affiliation(s)
- Zheng-Wei Cui
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China
| | - Lu-Lu Kong
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China; College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Fei Zhao
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.
| | - Ai-Ping Tan
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China
| | - Yu-Ting Deng
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China
| | - Lan Jiang
- Key Laboratory of Fishery Drug Development of Ministry of Agriculture and Rural Affairs, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China
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11
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Zhang Y, Yang C, Ge S, Wang L, Zhang J, Yang P. EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation. BMC Mol Cell Biol 2020; 21:29. [PMID: 32299362 PMCID: PMC7164363 DOI: 10.1186/s12860-020-00273-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 04/03/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Low concentrations of tumor necrosis factor-alpha (TNF-α) and its receptor TNFR2 are both reported to promote osteogenic differentiation of osteoblast precursor cells. Moreover, low concentrations of TNF-α up-regulate the expression of EphB4. However, the molecular mechanisms underlying TNF-α-induced osteogenic differentiation and the roles of TNFR2 and EphB4 have not been fully elucidated. RESULTS The ALP activity, as well as the mRNA and protein levels of RUNX2, BSP, EphB4 and TNFR2, was significantly elevated in MC3T3-E1 murine osteoblast precursor cells when stimulated with 0.5 ng/ml TNF-α. After TNFR2 was inhibited by gene knockdown with lentivirus-mediated shRNA interference or by a neutralizing antibody against TNFR2, the pro-osteogenic effect of TNF-α was partly reversed, while the up-regulation of EphB4 by TNF-α remained unchanged. With EphB4 forward signaling suppressed by a potent inhibitor of EphB4 auto-phosphorylation, NVP-BHG712, TNF-α-enhanced expressions of TNFR2, BSP and Runx2 were significantly decreased. Further investigation into the signaling pathways revealed that TNF-α significantly increased levels of p-JNK, p-ERK and p-p38. However, only the p-ERK level was significantly inhibited in TNFR2-knockdown cells. In addition, the ERK pathway inhibitor, U0126 (10 μM), significantly reversed the positive effect of TNF-α on the protein levels of RUNX2 and BSP. CONCLUSIONS The EphB4, TNFR2 and ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation.
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Affiliation(s)
- Yu Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China
| | - Chengzhe Yang
- Department of Oral & Maxillofacial Surgery, Qilu Hospital, Institute of Stomatology, Shandong University, No. 107 Wenhua Road West, Jinan, Shandong Province, China
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China
| | - Limei Wang
- Department of Oral Medicine, Qilu Hospital, Institute of Stomatology, Shandong University, No. 107 Wenhua Road West, Jinan, Shandong Province, China
| | - Jin Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China. .,Department of Endodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
| | - Pishan Yang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China. .,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.
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12
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Alshevskaya AA, Belomestnova I, Lopatnikova JA, Zhukova J, Evsegneeva I, Koneva O, Karaulov AV, Sennikov SV. Co-Expression of Membrane-Bound Tumor Necrosis Factor-Alpha Receptor Types 1 and 2 by Tumor Cell Lines. Int Arch Allergy Immunol 2020; 181:249-256. [PMID: 32036359 DOI: 10.1159/000505267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/06/2019] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION Density and co-expression of tumor necrosis factor (TNF) receptors may vary among cell populations. However, the role and potential of these changes remain unclear. This study aimed to determine the density of expression and co-expression of TNFR1/2 and the dose-dependent effect of soluble TNF on these parameters. METHODS Epithelial-like (HEp-2, K-562, MCF-7, ZR-75/1) and lymphoblast-like (MOLT-4, HL-60, Raji, RPMI-8226, IM-9) cell lines were characterized for co-expression of TNFR1/2 using a modified flow cytometry protocol. The dose-dependent effects of rhTNF on TNF receptor expression in these lines were studied. RESULTS This study reports a protocol for the simultaneous quantitative evaluation of the of TNF receptor number and co-expression of membrane-bound TNFR1/2. Cells within one tumor cell line were found to differ regarding their expression of type 1 and 2 TNFα receptors; simultaneously, cells with all 4 variants of co-expression may be present in culture. CONCLUSION We demonstrated a dose-dependent effect of TNF on changes in the expression of TNFR1/2 by the percentage of positive cells and by the number of receptors, which may be used to control TNF-mediated processes in target cells.
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Affiliation(s)
- Alina A Alshevskaya
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation
| | - Irina Belomestnova
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation
| | - Julia A Lopatnikova
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation
| | - Julia Zhukova
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation
| | - Irina Evsegneeva
- Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Olga Koneva
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation
| | - Aleksander V Karaulov
- Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Sergey Vitalievich Sennikov
- Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), Novosibirsk, Russian Federation, .,Novosibirsk State University, Novosibirsk, Russian Federation,
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13
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Todd L, Palazzo I, Suarez L, Liu X, Volkov L, Hoang TV, Campbell WA, Blackshaw S, Quan N, Fischer AJ. Reactive microglia and IL1β/IL-1R1-signaling mediate neuroprotection in excitotoxin-damaged mouse retina. J Neuroinflammation 2019; 16:118. [PMID: 31170999 PMCID: PMC6555727 DOI: 10.1186/s12974-019-1505-5] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 05/09/2019] [Indexed: 12/12/2022] Open
Abstract
Background Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage. Methods Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes. Results NMDA-induced damage included neuronal cell death, microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1β-signaling in different types of retinal neurons and glia. Expression of the IL1β receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Müller glia, and OFF bipolar cells. Ablation of microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1β stimulated the proliferation and reactivity of microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1β failed to provide neuroprotection in the IL-1R1-null retina, but IL1β-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes. Conclusions We conclude that reactive microglia provide protection to retinal neurons, since the absence of microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of microglia may be mediated by IL1β, IL-1R1, and interactions of microglia and other macroglia. Electronic supplementary material The online version of this article (10.1186/s12974-019-1505-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Levi Todd
- Department of Biological Structure, University of Washington, Seattle, WA, USA
| | - Isabella Palazzo
- Department of Neuroscience, College of Medicine, The Ohio State University, 3020 Graves Hall, 333 W. 10th Ave, Columbus, OH, 43210-1239, USA
| | - Lilianna Suarez
- Department of Neuroscience, College of Medicine, The Ohio State University, 3020 Graves Hall, 333 W. 10th Ave, Columbus, OH, 43210-1239, USA
| | - Xiaoyu Liu
- Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Leo Volkov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Thanh V Hoang
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Warren A Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, 3020 Graves Hall, 333 W. 10th Ave, Columbus, OH, 43210-1239, USA
| | - Seth Blackshaw
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ning Quan
- Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, USA.,Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA
| | - Andy J Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, 3020 Graves Hall, 333 W. 10th Ave, Columbus, OH, 43210-1239, USA.
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14
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Roy U. 3D Modeling of Tumor Necrosis Factor Receptor and Tumor Necrosis Factor-bound Receptor Systems. Mol Inform 2019; 38:e1800011. [PMID: 30632313 DOI: 10.1002/minf.201800011] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 12/04/2018] [Indexed: 01/25/2023]
Abstract
The interactions between the tumor necrosis factor (TNF) and its receptor molecule are responsible for various signaling networks that are central to the functioning of human immune homeostasis. The present work is a computational study of certain structural aspects of this cell-signaling protein, specifically focusing on the molecular level analyses of the TNF receptor (TNF-R), guided by its crystallographic structure. We also examine the possible binding sites of the TNF onto TNF-R, and the associated interactions. The structural and conformational variations in the TNF-R and TNF bound TNF-R systems are examined in this context using molecular dynamics (MD) simulations. The time dependent variations of the dimeric TNF-R structures are compared with, and shown to be steadier than their isolated monomers. This dimeric stability is favored under acidic conditions. The results are used to further illustrate how 3D modeling and computer simulations can aid the structure-based approach to probing a ligand-receptor system.
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Affiliation(s)
- Urmi Roy
- Department of Chemistry & Biomolecular Science, Clarkson University, 8 Clarkson Avenue, Potsdam, NY, 13699-5820, United States
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15
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Richter F, Zettlitz KA, Seifert O, Herrmann A, Scheurich P, Pfizenmaier K, Kontermann RE. Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity. MAbs 2019; 11:166-177. [PMID: 30252601 PMCID: PMC6343807 DOI: 10.1080/19420862.2018.1524664] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/29/2018] [Accepted: 09/10/2018] [Indexed: 01/08/2023] Open
Abstract
Selective inhibition of tumor necrosis factor (TNF) signaling through the proinflammatory axis of TNF-receptor 1 (TNFR1) while leaving pro-survival and regeneration-promoting signals via TNFR2 unaffected is a promising strategy to circumvent limitations of complete inhibition of TNF action by the approved anti-TNF drugs. A previously developed humanized antagonistic TNFR1-specific antibody, ATROSAB, showed potent inhibition of TNFR1-mediated cellular responses. Because the parental mouse antibody H398 possesses even stronger inhibitory potential, we scrutinized the specific binding parameters of the two molecules and revealed a faster dissociation of ATROSAB compared to H398. Applying affinity maturation and re-engineering of humanized variable domains, we generated a monovalent Fab derivative (13.7) of ATROSAB that exhibited increased binding to TNFR1 and superior inhibition of TNF-mediated TNFR1 activation, while lacking any agonistic activity even in the presence of cross-linking antibodies. In order to improve its pharmacokinetic properties, several Fab13.7-derived molecules were generated, including a PEGylated Fab, a mouse serum albumin fusion protein, a half-IgG with a dimerization-deficient Fc, and a newly designed Fv-Fc format, employing the knobs-into-holes technology. Among these derivatives, the Fv13.7-Fc displayed the best combination of improved pharmacokinetic properties and antagonistic activity, thus representing a promising candidate for further clinical development.
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Affiliation(s)
- Fabian Richter
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
| | - Kirstin A. Zettlitz
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Oliver Seifert
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | | | - Peter Scheurich
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
| | - Klaus Pfizenmaier
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
| | - Roland E. Kontermann
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
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16
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Hassanzad M, Farnia P, Ghanavi J, Parvini F, Saif S, Velayati AA. TNFα -857 C/T and TNFR2 +587 T/G polymorphisms are associated with cystic fibrosis in Iranian patients. Eur J Med Genet 2018; 62:103584. [PMID: 30472484 DOI: 10.1016/j.ejmg.2018.11.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 11/04/2018] [Accepted: 11/22/2018] [Indexed: 02/07/2023]
Abstract
Identification of modifier genes influencing phenotype of cystic fibrosis (CF) patients has become a challenge in CF pathophysiology, prognostic estimations and development of new therapeutic strategies. The aim of this study was to explore the association between four genetic polymorphisms of three modifier genes with CF, by comparing their alleles, genotypes and haplotype frequencies in patients and controls. In this favor, two regulatory polymorphic loci in TNFα promoter (-857C/T, rs1799724 and -238A/G, rs361525) and two functional polymorphic loci in TNFR1 (+36A/G, rs767455) and TNFR2 (+587T/G, rs1061622) were genotyped in 70 patients and 79 controls, using PCR-RFLP. Clinical pulmonary data were also recorded from all studied patients. Results indicated that an association was observed between both T allele and CT/TT genotypes of TNFα (P = 0.0005, OR = 7.06, 95% CI = 3.71-13.45) with CF under dominant model of inheritance. GG genotype of TNFR2 +587 (P = 0.0005, OR = 4.92, 95%CI = 2.34-10.34) was significantly associated with CF using recessive model. Consistently, more severe pulmonary disorder was found for patients carrying either T dominant allele of TNFα -857 or GG genotype of TNFR2 +587 polymorphic sites. Despite an association of A-T and G-T haplotypes with CF, no significant association was found between these haplotypes and clinical parameters of CF. Overall, TNFα -857 T allele and GG genotype of TNFR2 +587 were more frequent in CF patients compared to healthy controls and hence, they showed an association with CF and severe pulmonary phenotype in Iranian patients.
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Affiliation(s)
- Maryam Hassanzad
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Poopak Farnia
- Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Jalaledin Ghanavi
- Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Parvini
- Department of Cell and Molecular Biology, Faculty of Science, Semnan University, Semnan, Iran
| | - Shima Saif
- Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Velayati
- Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Tyrinova T, Leplina O, Mishinov S, Tikhonova M, Kalinovskiy A, Chernov S, Dolgova E, Stupak V, Voronina E, Bogachev S, Shevela E, Ostanin A, Chernykh E. Defective Dendritic Cell Cytotoxic Activity of High-Grade Glioma Patients' Results from the Low Expression of Membrane TNFα and Can Be Corrected In Vitro by Treatment with Recombinant IL-2 or Exogenic Double-Stranded DNA. J Interferon Cytokine Res 2018; 38:298-310. [PMID: 29932796 DOI: 10.1089/jir.2017.0084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Besides initiation of tumor-specific T cell immunity, dendritic cells (DCs) are endowed with tumoricidal activity. Previously, we showed that monocyte-derived DCs of high-grade glioma patients generated in the presence of interferon alpha (IFNα) (IFN-DCs) have impaired cytotoxic activity against tumor necrosis factor alpha (TNFα)-sensitive HEp-2 tumor cells. Herein, we demonstrate that decreased transmembrane TNFα (tmTNFα) expression, but not soluble TNFα (sTNFα) production by high-grade glioma patient IFN-DCs, determines the defective tumoricidal activity against TNFα-sensitive HEp-2 cells. Blocking TNFα-converting enzyme or stimulation of patient IFN-DCs with rIL-2 or dsDNA enhances tmTNFα expression on IFN-DCs and significantly increases their cytotoxicity. Decreased tmTNFα expression on patient IFN-DCs is not caused by downregulation of pNFκB. Neither rIL-2 nor dsDNA upregulates tmTNFα expression on patient IFN-DCs via an increase of pNFκB. The current study shows an important role of tmTNFα as mediator of IFN-DC tumoricidal activity and as molecular target for the restoration of defective DC killer activity in high-grade glioma patients.
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Affiliation(s)
- Tamara Tyrinova
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Olga Leplina
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Sergey Mishinov
- 2 Department of Neurosurgery, Novosibirsk Research Institute of Traumatology and Orthopedics named after Ya.L. Zivian , Novosibirsk, Russia
| | - Marina Tikhonova
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Anton Kalinovskiy
- 3 Department of Neurosurgery, Federal Neurosurgical Center , Novosibirsk, Russia
| | - Sergey Chernov
- 3 Department of Neurosurgery, Federal Neurosurgical Center , Novosibirsk, Russia
| | - Evgeniya Dolgova
- 4 Laboratory of Induced Cellular Processes, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk, Russia
| | - Vyacheslav Stupak
- 2 Department of Neurosurgery, Novosibirsk Research Institute of Traumatology and Orthopedics named after Ya.L. Zivian , Novosibirsk, Russia
| | - Evgeniya Voronina
- 5 Laboratory of Morphological and Molecular Biology Techniques, Regional Center of High Medical Technologies , Novosibirsk, Russia
| | - Sergey Bogachev
- 4 Laboratory of Induced Cellular Processes, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk, Russia
| | - Ekaterina Shevela
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Alexander Ostanin
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
| | - Elena Chernykh
- 1 Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology , Novosibirsk, Russia
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18
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Ye LL, Wei XS, Zhang M, Niu YR, Zhou Q. The Significance of Tumor Necrosis Factor Receptor Type II in CD8 + Regulatory T Cells and CD8 + Effector T Cells. Front Immunol 2018; 9:583. [PMID: 29623079 PMCID: PMC5874323 DOI: 10.3389/fimmu.2018.00583] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 03/08/2018] [Indexed: 01/03/2023] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4+Foxp3+ regulatory T cells (Tregs) and CD8+Foxp3+ Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8+ effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8+ Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor-associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8+Foxp3+ Tregs and CD8+ Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8+ T cell-mediated immune responses.
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Affiliation(s)
- Lin-Lin Ye
- Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Shan Wei
- Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Zhang
- Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Ran Niu
- Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Zhou
- Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy. Int J Biol Macromol 2018; 107:2113-2121. [DOI: 10.1016/j.ijbiomac.2017.10.078] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 10/06/2017] [Accepted: 10/13/2017] [Indexed: 12/21/2022]
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Abstract
PURPOSE OF REVIEW Current biomarkers for chronic kidney disease (CKD) are limited by lack of sensitivity and inability to prognosticate CKD progression. Significant recent research has better characterized novel biomarker candidates that are associated with CKD progression and cardiovascular mortality in CKD. This review discusses the most significant advances within the past year. RECENT FINDINGS We discuss biomarkers for outcomes in CKD under two categories: emerging (defined as having been validated in an independent cohort), which include serum cystatin C, serum β-trace protein, β2-microglobulin, soluble urokinase-type plasminogen activator receptor, soluble tumor necrosis factor receptors 1/2, urinary monocyte chemotactic protein-1, neutrophil gelatin-associated lipocalin, kidney injury molecule-1, and fibroblast growth factor-23; and novel (which have shown associations in smaller observational studies but have not been validated yet), which include indoxyl sulfate, p-cresyl sulfate, trimethylamine-N-oxide, IL-18, Klotho, markers of endothelial dysfunction, vimentin, and procollagen type III N-terminal propeptide. Further, we also discuss future directions for biomarker research including unbiased -omics approaches. SUMMARY There are a number of promising biomarkers that can better prognosticate outcomes in and progression of CKD. Further research is warranted to examine whether these biomarkers validate independently as well, and if their incorporation improves clinical practice or trial enrollment.
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21
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Ashwood P. Differential T Cell Levels of Tumor Necrosis Factor Receptor-II in Children With Autism. Front Psychiatry 2018; 9:543. [PMID: 30524316 PMCID: PMC6256095 DOI: 10.3389/fpsyt.2018.00543] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 10/11/2018] [Indexed: 11/13/2022] Open
Abstract
Autism spectrum disorders (ASD) are characterized by impairments in verbal and non-verbal communication, in social interactions, and often accompanied by stereotypical interests and behaviors. A role for immune dysfunction has long been implicated in ASD pathophysiology, behavioral severity, and co-morbidities. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been associated with ASD in some studies but little is known about its receptors. There are two receptors for TNFα, with TNFRI relaying many of the signals from TNFα, especially those that are rapid, whilst TNFRII relays later more long-term effects of TNFα. Proteolytic cleavage can lead to the soluble versions of these receptors which can neutralize the effects of TNFα. Here, we determined levels of TNFα and its receptors in 36 children with a confirmed diagnosis of ASD and 27 confirmed typically developing (TD) controls, 2-5 years-of-age. Children with ASD had higher levels of TNFRII on T cells compared to controls following cell stimulation. Levels of sTNFRII were decreased in cell supernatants following stimulation in ASD. Overall these data corroborate the role of inflammatory events in ASD and align with previous studies that have shown differential changes in cellular adaptive immunity in children with ASD. Future longitudinal analyzes of cellular immune function and downstream signaling from immune receptors will help further delineate the role of inflammation in ASD.
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Affiliation(s)
- Paul Ashwood
- Department of Medical Microbiology and Immunology, and The Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, CA, United States
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22
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Kirk GD, Dandorf S, Li H, Chen Y, Mehta SH, Piggott DA, Margolick JB, Leng SX. Differential Relationships among Circulating Inflammatory and Immune Activation Biomediators and Impact of Aging and Human Immunodeficiency Virus Infection in a Cohort of Injection Drug Users. Front Immunol 2017; 8:1343. [PMID: 29097998 PMCID: PMC5653695 DOI: 10.3389/fimmu.2017.01343] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 10/03/2017] [Indexed: 01/30/2023] Open
Abstract
As individuals with human immunodeficiency virus (HIV) infection live longer, aging and age-related chronic conditions have become major health concerns for this vulnerable population. Substantial evidence suggests that chronic inflammation and immune activation contribute significantly to chronic conditions in people aging with or without HIV infection. As a result, increasing numbers of inflammation and immune activation biomediators have been measured. While very few studies describe their in vivo relationships, such studies can serve as an important and necessary initial step toward delineating the complex network of chronic inflammation and immune activation. In this study, we evaluated in vivo relationships between serum levels of neopterin, a biomediator of immune activation, and four commonly described inflammatory biomediators: soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, sTNFR-2, interleukin (IL)-6, and C-reactive protein (CRP), as well as the impact of HIV infection and aging in the AIDS Linked to the Intravenous Experience (ALIVE) study, a community-recruited observational study of former and current injection drug users (IDUs) with or at high risk for HIV infection in Baltimore, MD, USA. The study included 1,178 participants in total with 316 HIV-infected (HV+) and 862 HIV-uninfected (HIV−) IDUs. Multivariate regression analyses were employed, adjusting for age, sex, body mass index, smoking, hepatitis C virus co-infection, injection drug use, comorbidities, and HIV status (for all participants), and HIV viral load, CD4+ T-cell counts, and antiretroviral therapy (for HIV+ participants). The results showed significant impact of aging on all five biomediators and that of HIV infection on all but sTNFR-1. In the adjusted model, neopterin had positive associations with sTNFR-1 and sTNFR-2 (partial correlation coefficients: 0.269 and 0.422, respectively, for all participants; 0.292 and 0.354 for HIV+; and 0.262 and 0.435 for HIV−, all p < 0.0001). No significant associations between neopterin and IL-6 or CRP were identified. Such differential relationships between circulating neopterin and sTNFR-1, sTNFR-2, IL-6, and CRP may help inform their selection in future studies. These findings may also facilitate elucidation of underlying inflammatory and immune activation pathways that contribute to age-related chronic conditions, potentially leading to identification of key biomediators, particularly those upstream of CRP, as novel targets for intervention.
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Affiliation(s)
- Gregory D Kirk
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.,Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Stewart Dandorf
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Huifen Li
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Yiyin Chen
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Shruti H Mehta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Damani A Piggott
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Joseph B Margolick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Sean X Leng
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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23
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Coca SG, Nadkarni GN, Huang Y, Moledina DG, Rao V, Zhang J, Ferket B, Crowley ST, Fried LF, Parikh CR. Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. J Am Soc Nephrol 2017; 28:2786-2793. [PMID: 28476763 PMCID: PMC5576932 DOI: 10.1681/asn.2016101101] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 03/29/2017] [Indexed: 11/03/2022] Open
Abstract
Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.
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Affiliation(s)
| | | | - Yuan Huang
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
- Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Dennis G Moledina
- Program of Applied Translational Research, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Veena Rao
- Program of Applied Translational Research, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Jane Zhang
- Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Bart Ferket
- Institute for Healthcare Delivery Science, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Susan T Crowley
- Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Linda F Fried
- Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and
- Epidemiology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Chirag R Parikh
- Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut;
- Program of Applied Translational Research, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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24
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Lin RL, Gu Q, Lee LY. Hypersensitivity of Vagal Pulmonary Afferents Induced by Tumor Necrosis Factor Alpha in Mice. Front Physiol 2017; 8:411. [PMID: 28659824 PMCID: PMC5470033 DOI: 10.3389/fphys.2017.00411] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 05/30/2017] [Indexed: 12/31/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) and vehicle (Veh; phosphate buffered saline (PBS), 0.03 ml) were administered by intra-tracheal instillation in each mouse of treated (TNF) and control (Veh) groups, respectively, the peak activity of pulmonary C-fibers in response to an intravenous bolus injection of a low dose of capsaicin (Cap; 0.5 μg/kg) was significantly elevated in TNF group (6.5 ± 1.3 impulses/s, n = 12) 24–48 h later, compared to that in Veh group (2.2 ± 0.5 impulses/s, n = 11; P < 0.05). Interestingly, the same low dose of Cap injection also evoked a distinct burst of discharge (2.4 ± 0.7 impulses/s) in 75% of the silent rapidly adapting receptors (RARs), a subtype of RARs exhibiting no phasic activity, in TNF group, but did not stimulate any of the silent RARs in Veh group. To further determine if this sensitizing effect involves a direct action of TNFα on these sensory nerves, the change in intracellular Ca2+ concentration in response to Cap challenge was measured in isolated mouse vagal pulmonary sensory neurons. The Cap-evoked Ca2+ influx was markedly enhanced in the neurons incubated with TNFα (50 ng/ml) for ~24 h, and this sensitizing effect was attenuated in the neurons isolated from the TNF-receptor double homozygous mutant mice. In conclusion, the TNFα pretreatment enhanced the Cap sensitivity in both pulmonary C-fibers and silent RARs, and the action was mediated through TNF receptors. These sensitizing effects of TNFα may contribute, at least in part, to the pathogenesis of airway hyperresponsiveness induced by this cytokine.
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Affiliation(s)
- Ruei-Lung Lin
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Qihai Gu
- Department of Biomedical Sciences, Mercer University, Macon, GA, United States
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky, Lexington, KY, United States
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25
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Lin RL, Gu Q, Khosravi M, Lee LY. Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways. Pulm Pharmacol Ther 2017; 47:29-37. [PMID: 28587842 DOI: 10.1016/j.pupt.2017.06.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/30/2017] [Accepted: 06/03/2017] [Indexed: 01/07/2023]
Abstract
Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 h later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and cytokines in the lung and airways. Accompanying these inflammatory reactions, the sensitivity of vagal pulmonary C-fibers and silent rapidly adapting receptors to capsaicin, a selective agonist of transient receptor potential vanilloid type 1 receptor, was markedly elevated after the TNFα treatment. A distinct increase in the sensitivity to capsaicin induced by TNFα was also observed in isolated pulmonary sensory neurons, suggesting that the sensitizing effect is mediated primarily through a direct action of TNFα on these neurons. Furthermore, the same TNFα treatment also induced a lingering (>7days) cough hyperresponsiveness to inhalation challenge of NH3 in awake mice. Both the airway inflammation and the sensitizing effect on pulmonary sensory neurons caused by the TNFα treatment were abolished in the TNF-receptor double homozygous mutant mice, indicating the involvement of TNF-receptor activation. These findings suggest that the TNFα-induced hypersensitivity of vagal bronchopulmonary afferents may be responsible for, at least in part, the airway hyperresponsiveness caused by inhaled TNFα in healthy individuals.
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Affiliation(s)
- Ruei-Lung Lin
- Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Qihai Gu
- Department of Biomedical Sciences, Mercer University, Macon, GA, USA
| | - Mehdi Khosravi
- Department of Medicine, University of Kentucky, Lexington, KY, USA
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky, Lexington, KY, USA.
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26
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Hsu CC, Lin YS, Lin RL, Lee LY. Immediate and delayed potentiating effects of tumor necrosis factor-α on TRPV1 sensitivity of rat vagal pulmonary sensory neurons. Am J Physiol Lung Cell Mol Physiol 2017; 313:L293-L304. [PMID: 28522561 DOI: 10.1152/ajplung.00235.2016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 05/05/2017] [Accepted: 05/06/2017] [Indexed: 01/19/2023] Open
Abstract
We studied acute effects of tumor necrosis factor-α (TNFα) on the sensitivity of isolated rat vagal pulmonary sensory neurons. Our results showed the following. First, a brief pretreatment with a low dose of TNFα (1.44 nM, 9 min) enhanced the sensitivity of transient receptor potential vanilloid type 1 (TRPV1) receptors in these neurons in two distinct phases: the inward current evoked by capsaicin was amplified (Δ = 247%) immediately following the TNFα pretreatment, which gradually declined toward control and then increased again reaching another peak (Δ = 384%) after 60-90 min. Second, the immediate phase of this potentiating effect of TNFα was completely abolished by a pretreatment with a selective cyclooxygenase-2 (COX-2) inhibitor, NS-398, whereas the delayed potentiation was only partially attenuated. Third, in sharp contrast, TNFα did not generate any potentiating effect on the responses to non-TRPV1 chemical activators of these neurons. Fourth, the selectivity of the TNFα action on TRPV1 was further illustrated by the responses to acid (pH 6.0); TNFα did not affect the rapid transient current mediated by acid-sensing ion channels but significantly augmented the slow sustained current mediated by TRPV1 in the same neurons. Fifth, in anesthetized rats, a similar pattern of acute sensitizing effects of TNFα on pulmonary C-fiber afferents and the involvement of COX-2 were also clearly shown. In conclusion, a brief pretreatment with TNFα induced both immediate and delayed potentiating effects on the TRPV1 sensitivity in pulmonary sensory neurons, and the production of COX-2 arachidonic acid metabolites plays a major role in the immediate sensitizing effect of TNFα.
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Affiliation(s)
- Chun-Chun Hsu
- Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky.,School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; and
| | - You Shuei Lin
- Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky.,Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ruei-Lung Lin
- Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky;
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27
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Eisenman ST, Gibbons SJ, Verhulst PJ, Cipriani G, Saur D, Farrugia G. Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers. Neurogastroenterol Motil 2017; 29:10.1111/nmo.12984. [PMID: 27781339 PMCID: PMC5367986 DOI: 10.1111/nmo.12984] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 09/20/2016] [Accepted: 09/28/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Delayed gastric emptying in diabetic mice and humans is associated with changes in macrophage phenotype and loss of interstitial cells of Cajal (ICC) in the gastric muscle layers. In diabetic mice, classically activated M1 macrophages are associated with delayed gastric emptying, whereas alternatively activated M2 macrophages are associated with normal gastric emptying. This study aimed to determine if secreted factors from M1 macrophages could injure mouse ICC in primary culture. METHODS Cultures of gastric ICC were treated with conditioned medium (CM) from activated bone marrow-derived macrophages (BMDMs) and the effect of CM was quantified by counting ICC per high-powered field. KEY RESULTS Bone marrow-derived macrophages were activated to a M1 or M2 phenotype confirmed by qRT-PCR. Conditioned medium from M1 macrophages reduced ICC numbers by 41.1%, whereas M2-CM had no effect as compared to unconditioned, control media. Immunoblot analysis of 40 chemokines/cytokines found 12 that were significantly increased in M1-CM, including tumor necrosis factor alpha (TNF-α). ELISA detected 0.697±0.03 ng mL-1 TNF-α in M1-CM. Recombinant mouse TNF-α reduced Kit expression and ICC numbers in a concentration-dependent manner (EC50 = 0.817 ng mL-1 ). Blocking M1-CM TNF-α with a neutralizing antibody preserved ICC numbers. The caspase inhibitor Z-VAD.fmk partly preserved ICC numbers (cells/field; 6.63±1.04, 9.82±1.80 w/Z-VAD.fmk, n=6, P<.05). CONCLUSIONS & INFERENCES This work demonstrates that TNF-α secreted from M1 macrophages can result in Kit loss and directly injure ICC in vitro partly through caspase-dependent apoptosis and may play an important role in ICC depletion in diabetic gastroparesis.
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Affiliation(s)
| | | | | | | | - Dieter Saur
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany
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28
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Späth F, Wibom C, Krop EJM, Johansson AS, Bergdahl IA, Vermeulen R, Melin B. Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis. Cancer Res 2017; 77:1408-1415. [PMID: 28108506 DOI: 10.1158/0008-5472.can-16-2345] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 11/16/2016] [Accepted: 12/05/2016] [Indexed: 11/16/2022]
Abstract
The B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker-disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10-10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408-15. ©2017 AACR.
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Affiliation(s)
- Florentin Späth
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
| | - Carl Wibom
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Esmeralda J M Krop
- Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands
| | | | | | - Roel Vermeulen
- Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands
| | - Beatrice Melin
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
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29
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Zhang S, Zhang R, Ma T, Qiu X, Wang X, Zhang A, Zhou H. Identification and functional characterization of tumor necrosis factor receptor 1 (TNFR1) of grass carp (Ctenopharyngodon idella). FISH & SHELLFISH IMMUNOLOGY 2016; 58:24-32. [PMID: 27620818 DOI: 10.1016/j.fsi.2016.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/14/2016] [Accepted: 09/08/2016] [Indexed: 06/06/2023]
Abstract
Tumor necrosis factor-alpha (TNF-α) exerts its regulatory effects by binding one of two TNF receptors, TNF-α receptor 1 (TNFR1) or TNFR2. In this study, we isolated and identified the cDNA sequence of grass carp TNFR1 (gcTNFR1). Similar to its homologs in other fish species, the putative protein of gcTNFR1 possessed an extracellular region containing three TNF homology domains, a transmembrane region and a cytoplasmic region with a conserved death domain. Consistent with the widespread expression of mammalian TNFR1, gcTNFR1 transcripts ubiquitously expressed in spleen, thymus, liver, heart, gill, intestine, brain and head kidney with the highest expression levels in head kidney. To reveal its inductive expression patterns in inflammatory response, effect of in vivo bacterial infection on gcTNFR1 gene expression was examined, showing a rapid increase of gcTNFR1 expression in head kidney, gill, liver and intestine, which is consistent with the role of TNF-α as an early response gene during immune challenges. To define the functional role of gcTNFR1, recombinant extracellular region of gcTNFR1 (rgcTNFR1) was prepared and used to perform in vitro binding assay, demonstrating its ability to interact with recombinant grass carp TNF-α (rgcTNF-α). Furthermore, to characterize the function of gcTNFR1 in affecting rgcTNF-α actions, the effect of overexpressing gcTNFR1 on rgcTNF-α-induced grass carp IL-1β (gcIL-1β) promoter activity was determined in COS7 cells. Results showed that gcTNFR1 was involved in the regulation of rgcTNF-α on gcIL-1β transcription. Consistently, rgcTNFR1 was effective in attenuating the effect of rgcTNF-α on IL-1β mRNA expression in grass carp head kidney leukocytes, providing evidence for the involvement of TNFR1 in TNF-α signaling in grass carp. These data facilitate a better understanding of TNF-α receptor signaling in grass carp.
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MESH Headings
- Aeromonas hydrophila/physiology
- Amino Acid Sequence
- Animals
- Carps/classification
- Carps/genetics
- Carps/immunology
- DNA, Complementary/genetics
- DNA, Complementary/metabolism
- Fish Diseases/genetics
- Fish Diseases/immunology
- Fish Diseases/microbiology
- Fish Proteins/chemistry
- Fish Proteins/genetics
- Fish Proteins/metabolism
- Gene Expression Regulation
- Gram-Negative Bacterial Infections/genetics
- Gram-Negative Bacterial Infections/immunology
- Gram-Negative Bacterial Infections/microbiology
- Gram-Negative Bacterial Infections/veterinary
- Head Kidney/immunology
- Immunity, Innate/genetics
- Leukocytes/immunology
- Phylogeny
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Tumor Necrosis Factor, Type I/chemistry
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Sequence Alignment
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Affiliation(s)
- Shengnan Zhang
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Rui Zhang
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Tengyue Ma
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Xingyang Qiu
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Xinyan Wang
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Anying Zhang
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China
| | - Hong Zhou
- School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China.
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Zhao XL, Tian LF, Zhang SJ, Li JM, Feng H, Wang LM, Wang S, Wang J, Wang T, Chen WQ. Novel Human Three-Domain Antibody Fragments Against sTNFα as Well as tmTNFα with High Affinity Generated by the Combination of Ribosome Display and E. coli Expression System. Scand J Immunol 2016; 83:267-78. [PMID: 26860639 DOI: 10.1111/sji.12417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/30/2016] [Indexed: 12/31/2022]
Abstract
Human tumour necrosis factor α (hTNFα) has been proved to be a validated therapeutic target in a number of immune-mediated inflammatory diseases (IMIDs). Fully human monoclonal antibodies (mAbs) that can neutralize soluble hTNFα (sTNFα) as well as transmembrane hTNFα (tmTNFα) are more desirable hTNFα antagonists. Here, we report that novel anti-hTNFα human low-molecular-weight MAbs have been selected and identified using both sTNFα and tmTNFα as target antigens by the combination of ribosome display and E. coli expression system for the first time. As a newly born engineering small molecular antibody, three-domain antibody fragment (VH /κ) provides an alternative promising molecular principle to generate biological agents for TNFα-dependent IMIDs. In this study, a panel of novel human VH /κs (F09, F21, F49 and F409) with high affinity (10(-10) -10(-9) mol/l) to neutralize sTNFα as well as tmTNFα was generated by the combination of ribosome display and E. coli expression system. Among the four clones, F21 and F409 could reduce cytotoxicity on L929 cells induced by sTNFα as well as tmTNFα effectively, and both of them had great potential to inhibit hTNFα-mediated NF-κB activation. Soluble F21 and F409 were also able to inhibit the binding of hTNFα to TNFR1 and TNFR2. The new human antibodies described here have desirable capability to neutralize sTNFα as well as tmTNFα effectively with high affinity and reasonable stability; this may provide an alternative approach for patients who are not responding adequately to currently available anti-TNFα agents.
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Affiliation(s)
- X-L Zhao
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China.,New York University School of Medicine, New York, NY, USA
| | - L-F Tian
- 1st hospital of ShanXi Medical University, Taiyuan, China
| | | | - J-M Li
- 254th Hospital, Tianjin, China
| | - H Feng
- Tianjin College of Physical Education, Tianjin, China
| | - L-M Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - S Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - J Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - T Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - W-Q Chen
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
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31
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Inoue N, Watanabe M, Ishido N, Kodu A, Maruoka H, Katsumata Y, Hidaka Y, Iwatani Y. Involvement of genes encoding apoptosis regulatory factors (FAS, FASL, TRAIL, BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases. Hum Immunol 2016; 77:944-951. [PMID: 27458112 DOI: 10.1016/j.humimm.2016.07.232] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 06/27/2016] [Accepted: 07/21/2016] [Indexed: 11/25/2022]
Abstract
Apoptosis is necessary for the maintenance of self-tolerance by eliminating autoreactive immune cells in the periphery. To clarify the association between the pathogenesis of autoimmune thyroid disease (AITD) and genes encoding apoptosis regulatory factors, we genotyped the FAS -1377G/A, -670A/G, FASL -844C/T, TRAIL -716C/T, BCL2 -938C/A, +127G/A, TNFR1 -383A/C and TNFR2 +676T/G polymorphisms. The frequencies of the FASL -844CC and BCL2 -938AA genotypes were significantly lower in AITD patients than in control subjects (P=0.0101 and 0.0307, respectively). The frequency of the TNFR2 +676TT genotype was significantly lower in Graves' disease (GD) patients than in controls (P=0.0284). The serum sFasL level was significantly higher in GD and Hashimoto's disease (HD) patients than in control subjects (P=0.0003 and 0.0017, respectively). The serum sFasL levels in control subjects were significantly lower than those in intractable GD, GD in remission, and HD without treatment (P=0.0310, 0.0007 and 0.0002, respectively). The serum sFasL levels in HD with treatment were significantly lower than those in HD without treatment (P=0.0490). The polymorphisms in genes encoding apoptosis regulatory factors (FASL, BCL2) and serum levels of sFasL may be associated with immune dysregulation.
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Affiliation(s)
- Naoya Inoue
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory for Clinical Investigation, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Mikio Watanabe
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Naoko Ishido
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Arisa Kodu
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hayato Maruoka
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yuka Katsumata
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yoh Hidaka
- Laboratory for Clinical Investigation, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yoshinori Iwatani
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University, Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
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32
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Tilz GP, Diez-Ruiz A, Baier-Bitterlich G, Demel U, Wachter H, Fuchs D. Soluble Receptors for Tumor Necrosis Factor and Neopterin as Parameters of Cell-Mediated Immune Activation. Hematology 2016; 1:141-54. [DOI: 10.1080/10245332.1996.11746298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Gernot P. Tilz
- Department of Internal Medicine, University of Graz, Graz, Austria Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
| | - Antonio Diez-Ruiz
- Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
| | - Gabriele Baier-Bitterlich
- Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
| | - Ulrike Demel
- Department of Internal Medicine, University of Graz, Graz, Austria Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
| | - Helmut Wachter
- Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
| | - Dietmar Fuchs
- Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria
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33
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Justus SJ, Ting AT. Cloaked in ubiquitin, a killer hides in plain sight: the molecular regulation of RIPK1. Immunol Rev 2016; 266:145-60. [PMID: 26085213 DOI: 10.1111/imr.12304] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the past decade, studies have shown how instrumental programmed cell death (PCD) can be in innate and adaptive immune responses. PCD can be a means to maintain homeostasis, prevent or promote microbial pathogenesis, and drive autoimmune disease and inflammation. The molecular machinery regulating these cell death programs has been examined in detail, although there is still much to be explored. A master regulator of programmed cell death and innate immunity is receptor-interacting protein kinase 1 (RIPK1), which has been implicated in orchestrating various pathologies via the induction of apoptosis, necroptosis, and nuclear factor-κB-driven inflammation. These and other roles for RIPK1 have been reviewed elsewhere. In a reflection of the ability of tumor necrosis factor (TNF) to induce either survival or death response, this molecule in the TNF pathway can transduce either a survival or a death signal. The intrinsic killing capacity of RIPK1 is usually kept in check by the chains of ubiquitin, enabling it to serve in a prosurvival capacity. In this review, the intricate regulatory mechanisms responsible for restraining RIPK1 from killing are discussed primarily in the context of the TNF signaling pathway and how, when these mechanisms are disrupted, RIPK1 is free to unveil its program of cellular demise.
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Affiliation(s)
- Scott J Justus
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, New York, NY, USA.,Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adrian T Ting
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, New York, NY, USA
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34
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Tassi Yunga S, Thévenon AD, Leke RGF, Taylor DW. Soluble Tumor Necrosis Factor-α Receptor 2 in Urine Is a Potential Biomarker for Noninvasive Diagnosis of Malaria During Pregnancy. Open Forum Infect Dis 2016; 3:ofw084. [PMID: 27419160 PMCID: PMC4943558 DOI: 10.1093/ofid/ofw084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/20/2016] [Indexed: 11/26/2022] Open
Abstract
Background. During pregnancy, the placenta is inaccessible for diagnosis of placental malaria (PM), but soluble tumor necrosis factor-α receptors (sTNFR) are elevated in the plasma of women with PM. Methods. In this study, sTNFR-1 and sTNFR-2 were quantified in urine of pregnant and nonpregnant Cameroonian women who were positive or negative for malaria by blood-smear microscopy. Results. We found that levels of both sTNFR in urine were higher in pregnant compared with nonpregnant women, but malaria-positive pregnant women excreted substantially more sTNFR-1 (P = .005) and sTNFR-2 (P < .001) than malaria-negative pregnant women. The amount of sTNFR-1(rs = 0.784, P < .001) and sTNFR-2 (rs = 0.816, P < .001) in urine correlated with parasitemia, even in afebrile pregnant women. Urine sTNFR-2 predicted maternal malaria with an area under curve of 0.892 (95% confidence interval, .787–.898). At cutoff concentrations of 9.8 ng and 13.6 ng of sTNFR-2 per mL urine, the sensitivity/specificity were 82.6%/87.0% and 78.3%/95.7%, respectively. Conclusions. The sTNFR-2 in noninvasive urine samples may be useful for diagnosis of malaria during pregnancy.
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Affiliation(s)
- Samuel Tassi Yunga
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu; The Biotechnology Center, University of Yaoundé 1, Cameroon
| | - Audrey Davidson Thévenon
- Department of Tropical Medicine, Medical Microbiology and Pharmacology , John A. Burns School of Medicine, University of Hawaii at Manoa , Honolulu
| | | | - Diane Wallace Taylor
- Department of Tropical Medicine, Medical Microbiology and Pharmacology , John A. Burns School of Medicine, University of Hawaii at Manoa , Honolulu
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35
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Ifergane G, Ovanyan A, Toledano R, Goldbart A, Abu-Salame I, Tal A, Stavsky M, Novack V. Obstructive Sleep Apnea in Acute Stroke: A Role for Systemic Inflammation. Stroke 2016; 47:1207-12. [PMID: 27073238 DOI: 10.1161/strokeaha.115.011749] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 03/14/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND PURPOSE Sleep-disordered breathing is common among patients with stroke resulting in 4- to 6-fold higher prevalence of obstructive sleep apnea (OSA). We prospectively evaluated clinical characteristics and laboratory markers of inflammation and coagulability associated with OSA severity during the acute post stroke period. METHODS Consecutive patients admitted to the department of Neurology after an acute ischemic stroke were evaluated during the first 48 hours of symptom onset using Watch peripheral arterial tonometry, a wrist-worn ambulatory sleep study device that utilizes peripheral arterial tonometry. Morning blood samples of the patient were tested for tumor necrosis factor, interleukin-6, and plasminogen activator inhibitor-1 levels. RESULTS A total of 43 patients with acute stroke were admitted during the study period, 22 (51%) of which have been found to have moderate sleep apnea (apnea hypopnea index [AHI]≥15), AHI≥5 was found in 86% of the patients, and severe OSA (AHI≥30) in 32.5%. Patients with OSA (AHI≥15) did not differ from the rest in stroke severity or symptoms, yet they had higher prevalence of recurrent stroke and atrial fibrillation. All 3 biomarkers levels were higher among patients with AHI≥15: tumor necrosis factor (6.39 versus 3.57 pg/mL), interleukin-6 (6.64 versus 3.14 pg/mL), and plasminogen activator inhibitor-1 (176.64 versus 98.48 pg/mL). After the stratification of AHI into 3 groups (AHI<5, 5-14, and ≥15), the analysis showed that only the highest AHI group differed from the other 2 groups in biomarkers levels. CONCLUSIONS Use of bed-side somnography technology revealed that in an unselected sample of patients with acute ischemic stroke, almost 90% had sleep-disordered breathing with third having severe form of the disorder. Sleep-disordered breathing was associated with significantly increased levels of inflammatory biomarkers, providing possible pathophysiological explanation of OSA-associated stroke risk. These results warrant prospective screening of patients with stroke for the presence of sleep-disordered breathing and lay the rationale for an interventional trial.
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Affiliation(s)
- Gal Ifergane
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.).
| | - Andrey Ovanyan
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Ronen Toledano
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Aviv Goldbart
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Ibrahim Abu-Salame
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Asher Tal
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Moshe Stavsky
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
| | - Victor Novack
- From the Department of Neurology (G.I., A.O., I.A.-S.), Clinical Research Center (R.T., M.S., V.N.), and Department of Pediatrics (A.G., A.T.), Soroka University Medical Center, Be'er-Sheva, Israel; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (G.I., A.O., R.T., A.G., I.A.-S., A.T., M.S., V.N.)
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TNFα triggers release of extracellular vesicles containing TNFR1 and TRADD, which can modulate TNFα responses of the parental cells. Arch Biochem Biophys 2015; 587:31-7. [DOI: 10.1016/j.abb.2015.10.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/09/2015] [Accepted: 10/10/2015] [Indexed: 01/11/2023]
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37
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Palanisamy R, Kumaresan V, Harikrishnan R, Arasu MV, Al-Dhabi NA, Arockiaraj J. Functional roles and gene regulation of tumor necrosis factor receptor 1 in freshwater striped murrel. Mol Immunol 2015; 66:240-252. [PMID: 25841174 DOI: 10.1016/j.molimm.2015.03.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 03/14/2015] [Accepted: 03/15/2015] [Indexed: 01/16/2023]
Abstract
In this study, a complete molecular characterization of tumor necrosis factor receptor 1 (TNFR1) which was identified from the constructed cDNA library of striped murrel Channa striatus (Cs) is reported. The CsTNFR1 encoded a type I membrane receptor protein that contains 399 amino acids including three cysteine-rich domains (CRDs) at CRD1(41-46), CRD2(79-118) and CRD3(120-159) in the extracellular region and a putative TNF receptor-associated factor (TRAF) site at 245-253 and a death domain between 297 and 388 in the cytoplasmic region which is essential for induction of apoptosis. The predicted molecular mass of CsTNFR1 is 45kDa and its corresponding theoretical isoelectric point (pI) is 6.3. CsTNFR1 shared maximum identity with TNFR1 from olive flounder Paralichthys olivaceus (82%). Real-time PCR showed that CsTNFR1 gene was expressed most abundantly (P<0.05) in the head kidney. Further, CsTNFR1 mRNA transcription was studied after challenge with fungus Apanomyces invadans and bacteria Aeromonas hydrophila. The fungus injected murrels showed a highest expression at 48h, whereas bacteria injected murrels showed at 24h. The gene expression studies revealed that CsTNFR1 may be involved in innate immune process of murrels against pathogenic infections. The over-expressed and purified recombinant CsTNFR1 protein (rCsTNFR1) was subjected to TNF-α inhibition assay to confirm their specificity and activity against TNF-α which confirmed that the rCsTNFR1 inhibits the activity of TNF-α in a dose dependent manner where maximum inhibition (97%) was observed at 10,000 fold concentration of rCsTNFR1. In addition, the direct cytotoxic effect of rCsTNFR1 was analyzed against head kidney phagocyte. The results showed that the recombinant CsTNFR1 protein does not exhibit any significant cytotoxicity against head kidney phagocyte cells even at higher concentration (8μg/ml). Moreover, the recombinant protein was analyzed for respiratory burst activity in the presence of two different ROS inducers, opsonized zymosan (fungal cell wall component) and phorbol 12-myristate 13-acetate (PMA). The findings showed that the C. striatus head kidney phagocyte exposed to purified recombinant CsTNFR1 protein alone do not produced any ROS. However, opsonized zymosan induced recombinant CsTNFR1 protein significantly (P<0.05) enhanced the ROS production on concentration basis which is revealed that the ROS production depends on the concentration of the recombinant CsTNFR1 protein. Overall, the study showed that the CsTNFR1 plays an important role in the pathogen-induced inflammatory process of striped murrel.
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MESH Headings
- Aeromonas hydrophila/immunology
- Amino Acid Sequence
- Animals
- Base Sequence
- Fish Diseases/immunology
- Fish Diseases/microbiology
- Fish Proteins/chemistry
- Fish Proteins/genetics
- Fish Proteins/immunology
- Fish Proteins/pharmacology
- Fishes/immunology
- Fishes/microbiology
- Gene Expression Regulation
- Gram-Negative Bacterial Infections/immunology
- Gram-Negative Bacterial Infections/microbiology
- Gram-Negative Bacterial Infections/veterinary
- Immunity, Innate
- Kidney/drug effects
- Kidney/immunology
- Kidney/microbiology
- Molecular Sequence Data
- Molecular Weight
- Mycoses/immunology
- Mycoses/microbiology
- Mycoses/veterinary
- Open Reading Frames
- Phagocytes/cytology
- Phagocytes/drug effects
- Phagocytes/immunology
- Protein Structure, Tertiary
- Reactive Oxygen Species/immunology
- Reactive Oxygen Species/metabolism
- Receptors, Tumor Necrosis Factor, Type I/chemistry
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/immunology
- Receptors, Tumor Necrosis Factor, Type I/pharmacology
- Recombinant Proteins/chemistry
- Recombinant Proteins/genetics
- Recombinant Proteins/immunology
- Recombinant Proteins/pharmacology
- Sequence Alignment
- Tetradecanoylphorbol Acetate/pharmacology
- Zymosan/pharmacology
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Affiliation(s)
- Rajesh Palanisamy
- Division of Fisheries Biotechnology & Molecular Biology, Department of Biotechnology, Faculty of Science and Humanities, SRM University, Kattankulathur 603 203, Chennai, Tamil Nadu, India
| | - Venkatesh Kumaresan
- Division of Fisheries Biotechnology & Molecular Biology, Department of Biotechnology, Faculty of Science and Humanities, SRM University, Kattankulathur 603 203, Chennai, Tamil Nadu, India
| | - Ramasamy Harikrishnan
- Department of Zoology, Pachaiyappa's College for Men, Kanchipuram 631 501, Tamil Nadu, India
| | - Mariadhas Valan Arasu
- Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Naif Abdullah Al-Dhabi
- Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Jesu Arockiaraj
- Division of Fisheries Biotechnology & Molecular Biology, Department of Biotechnology, Faculty of Science and Humanities, SRM University, Kattankulathur 603 203, Chennai, Tamil Nadu, India.
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Shey MS, Garrett NJ, McKinnon LR, Passmore JAS. The role of dendritic cells in driving genital tract inflammation and HIV transmission risk: are there opportunities to intervene? Innate Immun 2015; 21:99-112. [PMID: 24282122 PMCID: PMC4033703 DOI: 10.1177/1753425913513815] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Effective prevention of new HIV infections will require an understanding of the mechanisms involved in HIV acquisition. HIV transmission across the female genital tract is the major mode of new HIV infections in sub-Saharan Africa and involves complex processes, including cell activation, inflammation and recruitment of HIV target cells. Activated CD4(+) T-cells, dendritic cells (DC) and macrophages have been described as targets for HIV at the genital mucosa. Activation of these cells may occur in the presence of sexually-transmitted infections, disturbances of commensal flora and other inflammatory processes. In this review, we discuss causes and consequences of inflammation in the female genital tract, with a focus on DC. We describe the central role these cells may play in facilitating or preventing HIV transmission across the genital mucosa, and in the initial recognition of HIV and other pathogens, allowing activation of an adaptive immune response to infection. We discuss studies that investigate interventions to limit DC activation, inflammation and HIV transmission. This knowledge is essential in the development of novel strategies for effective HIV control, including microbicides and pre-exposure prophylaxis.
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Affiliation(s)
| | | | | | - Jo-Ann S Passmore
- CAPRISA, Durban, South Africa Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa National Health Laboratory Service, Cape Town, South Africa
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39
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Cabal-Hierro L, Artime N, Iglesias J, Prado MA, Ugarte-Gil L, Casado P, Fernández-García B, Darnay BG, Lazo PS. A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1. Oncotarget 2014; 5:224-36. [PMID: 24318359 PMCID: PMC3960203 DOI: 10.18632/oncotarget.1492] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.
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Affiliation(s)
- Lucía Cabal-Hierro
- Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
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TRAF-mediated modulation of NF-kB AND JNK Activation by TNFR2. Cell Signal 2014; 26:2658-66. [DOI: 10.1016/j.cellsig.2014.08.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 08/15/2014] [Indexed: 12/14/2022]
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TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney Int 2014; 87:281-96. [PMID: 25140911 DOI: 10.1038/ki.2014.285] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/28/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022]
Abstract
Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders.
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Kumar A, Devi SG, Kar P, Agarwal S, Husain SA, Gupta RK, Sharma S. Association of cytokines in hepatitis E with pregnancy outcome. Cytokine 2014; 65:95-104. [PMID: 24416783 DOI: 10.1016/j.cyto.2013.09.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS The aim of this study was to evaluate tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6, interferon gamma (IFN-γ) and transforming growth factor-beta1 (TGF-β1) in hepatitis E infection during pregnancy and its relation with pregnancy outcome. METHODS A total of 272 pregnant and 219 non-pregnant women with hepatitis and 262 age and gestational age matched healthy pregnant women and 208 age matched, healthy non-pregnant women were evaluated on the basis of history, clinical examination, liver function profile. Serological tests of hepatitis A, B, C and E and cytokines using commercially available (ELISA) kits. The patients with hepatitis E were further evaluated for viral load by Real Time PCR. All these were followed till delivery for pregnancy outcome. RESULTS HEV viral load in acute viral hepatitis (AVH) and fulminant hepatic failure (FHF) of pregnant women were comparatively higher than non-pregnant women. Significantly higher levels of TNF-α, IL-6, IFN-γ and TGF-β1 were present in HEV infected pregnant women compared to non-pregnant women and controls. TNF-α, IL-6 and IFN-γ had significant positive correlation with viral load, serum bilirubin and prothrombin time in pregnant women. Higher levels of all four cytokines were found in pregnant women with HEV infection having adverse pregnancy outcome compared to that of pregnant women with non-HEV infection and controls. CONCLUSION In conclusion, severity of HEV infection and associated adverse pregnancy outcome might be mediated by cytokine in pregnancy.
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Sasi SP, Song J, Park D, Enderling H, McDonald JT, Gee H, Garrity B, Shtifman A, Yan X, Walsh K, Natarajan M, Kishore R, Goukassian DA. TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells. J Biol Chem 2014; 289:14178-93. [PMID: 24711449 DOI: 10.1074/jbc.m114.567743] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
TNF-α, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body γ-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1-5 h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3-5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γ-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC γ-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-α and rmIL-1α, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general.
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Affiliation(s)
- Sharath P Sasi
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135
| | - Jin Song
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135
| | - Daniel Park
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135
| | - Heiko Enderling
- the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - J Tyson McDonald
- the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Hannah Gee
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135
| | - Brittany Garrity
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135
| | - Alexander Shtifman
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Xinhua Yan
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Kenneth Walsh
- the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118
| | - Mohan Natarajan
- the University of Texas Health Science Center, San Antonio, Texas 78229, and
| | - Raj Kishore
- the Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois 60611
| | - David A Goukassian
- From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111, the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118,
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Polymorphisms in the tumor necrosis factor receptor genes affect the expression levels of membrane-bound type I and type II receptors. Mediators Inflamm 2014; 2014:745909. [PMID: 24782596 PMCID: PMC3982480 DOI: 10.1155/2014/745909] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 01/23/2014] [Accepted: 02/02/2014] [Indexed: 11/17/2022] Open
Abstract
The level of TNF receptors on various cells of immune system and its association with the gene polymorphism were investigated. Determining the levels of membrane-bound TNFα receptors on peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry using BD QuantiBRITE calibration particles. Soluble TNFα receptor (sTNFRs) levels were determined by ELISA and genotyping was determined by PCR-RFLP. Homozygous TT individuals at SNP −609G/T TNFRI (rs4149570) showed lower levels of sTNFRI compared to GG genotype carriers. Homozygous carriers of CC genotype at SNP −1207G/C TNFRI (rs4149569) had lower expression densities of membrane-bound TNFRI on intact CD14+ monocytes compared to individuals with the GC genotype. The frequency differences in the CD3+ and CD19+ cells expressing TNFRII in relation to SNP −1709A/T TNFRII (rs652625) in healthy individuals were also determined. The genotype CC in SNP −3609C/T TNFRII (rs590368) was associated with a lower percentage of CD14+ cells expressing TNFRII compared to individuals with the CT genotype. Patients with rheumatoid arthritis had no significant changes in the frequencies of genotypes. Reduced frequency was identified for the combination TNFRI −609GT + TNFRII −3609CC only. The polymorphisms in genes represent one of cell type-specific mechanisms affecting the expression levels of membrane-bound TNFα receptors and TNFα-mediated signaling.
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Fricke F, Malkusch S, Wangorsch G, Greiner JF, Kaltschmidt B, Kaltschmidt C, Widera D, Dandekar T, Heilemann M. Quantitative single-molecule localization microscopy combined with rule-based modeling reveals ligand-induced TNF-R1 reorganization toward higher-order oligomers. Histochem Cell Biol 2014; 142:91-101. [DOI: 10.1007/s00418-014-1195-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2014] [Indexed: 11/27/2022]
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Dietz MS, Fricke F, Krüger CL, Niemann HH, Heilemann M. Receptor-Ligand Interactions: Binding Affinities Studied by Single-Molecule and Super-Resolution Microscopy on Intact Cells. Chemphyschem 2013; 15:671-6. [DOI: 10.1002/cphc.201300755] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Gutierrez-Gonzalez LA, Gudiño MAR, Ceija IO, Leonet MM, Noguera ZT. Efficacy and Safety of Rituximab in Biologic-Naive Patients with Rheumatoid Arthritis vs Anti-Tnf Therapy Failure. Open Rheumatol J 2013; 7:81-6. [PMID: 24179556 PMCID: PMC3812784 DOI: 10.2174/1874312920130913004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 07/16/2013] [Accepted: 07/16/2013] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVES Our aim was to compare an AntiCD20 therapy (rituximab) for rheumatoid arthritis in two patient populations (Group 1), anti-TNFα naïve patients and inadequate responders to Anti-TNFα therapy (Group 2). METHODS We analyzed the efficacy of the drug Rituximab (RTX) in RA patients who failed methotrexate (MTX) or had a relative or absolute contraindication to receive anti-TNFα therapy. RESULTS 25 patients were identified according to the above criteria and followed up for a mean period of 6 months. Thirteen patients were biologic naïve and twelve patients had already failed anti-TNFα therapy. Group 1 used 2> DMARDs (32% vs 20%, p<0.005), group 2 had more years of disease progression (5±1.89 v s4.10±3.92, p<0.001). The remission as measured by the DAS28 reached faster in group 1 (1.25±0.12 vs 2.15±1.64, p<0,001). Severe infections especially by herpes viruses were more frequent in group 2. CONCLUSIONS Comparing clinical improvement in both groups the decrease of acute phase reactants and the clinical remission measured by DAS28 was reached in both groups, however it was reached more belatedly in group 2 (at 6 months), this is due to the fact that they have more years of the disease evolution and a higher HAQ.
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Nadeem R, Molnar J, Madbouly EM, Nida M, Aggarwal S, Sajid H, Naseem J, Loomba R. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med 2013; 9:1003-12. [PMID: 24127144 DOI: 10.5664/jcsm.3070] [Citation(s) in RCA: 347] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
STUDY OBJECTIVES Obstructive sleep apnea (OSA) has been linked to and is associated with increased cardiovascular and cerebrovascular morbidity. Ongoing inflammatory responses play an important role in this association. Multiple small size studies addressing the profile of the inflammatory markers in OSA are available therefore we performed a meta-analysis. METHODS Systematic review of medical literature was conducted using PubMed, Cochrane, and EMBASE databases from 1968 to 2011 by utilizing the key words obstructive sleep apnea, C-Reactive protein, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and Selectins. Inclusion criteria were: full text English articles; studies with adult population; reported values for at least one of the markers of interest; with at least two separate groups (subjects with OSA and control group); OSA was defined as AHI of ≥ 5/h. RESULTS Five hundred and twelve studies were reviewed for inclusion with 51 studies pooled for analysis (30 studies for CRP, 19 studies for TNF-α, 8 studies for ICAM, 18 studies for IL-6, six studies for VCAM and 5 studies for Selectins). The levels of inflammatory markers were higher in patients with OSA compared to control group. Standardized pooled Mean differences were calculated to be 1.77 for CRP, 1.03 for TNF-α, 2.16 for IL-6, 4.22 for IL-8, 2.93 for ICAM, 1.45 for Selectins and 2.08 for VCAM. CONCLUSIONS In this meta-analysis, the levels of systemic inflammatory markers were found to be higher in OSA patients compared to control subjects.
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Affiliation(s)
- Rashid Nadeem
- Captain James A. Lovell Federal Health Care Centre, North Chicago, IL ; Rosalind Franklin University of Medicine and Science/ Chicago Medical School, North Chicago, IL
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Chhabra JK, Chattopadhyay B, Paul BN. SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling. Cell Mol Immunol 2013; 11:105-6. [PMID: 24037182 DOI: 10.1038/cmi.2013.36] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 07/02/2013] [Accepted: 07/04/2013] [Indexed: 11/09/2022] Open
Abstract
Tumor-necrosis factor-α (TNF-α)-driven nuclear factor-κB (NF-κB) activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-α is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-α signaling and that emergence of suppressor of cytokine signaling 3 (SOCS3) expression limits the ongoing NF-κB activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-α (50 ng/ml) induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-κB subunit and enhanced apoptosis, as shown by DNA laddering, annexin V positivity, and overexpression of caspase-3 and Bax in the late phase, whereas the early phase was marked by NF-κB activation. Conversely, SOCS3 knockdown by small interfering RNA (siRNA) inhibited granulocyte apoptosis and enhanced nuclear accumulation of p65 and 5' lipooxygenase expression in the late phase of TNF-α signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-α-driven events are time-phased, interconnected, opposing control mechanisms and one of the central features through which the immune system resolves pulmonary inflammation. Dysregulation may initiate mucosal inflammation, thus changing the landscape of asthma therapy.
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Affiliation(s)
- Jasmeet Kaur Chhabra
- Immunobiology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India
| | | | - Bhola Nath Paul
- Immunobiology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India
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Antagonistic TNF receptor one-specific antibody (ATROSAB): receptor binding and in vitro bioactivity. PLoS One 2013; 8:e72156. [PMID: 23977237 PMCID: PMC3747052 DOI: 10.1371/journal.pone.0072156] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 07/07/2013] [Indexed: 12/31/2022] Open
Abstract
Background Selective inhibition of TNFR1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, while leaving TNFR2 untouched, thus allowing for cell survival and tissue homeostasis. ATROSAB is a humanized antagonistic anti-TNFR1 antibody developed for the treatment of inflammatory diseases. Methodology/Principal Findings The epitope of ATROSAB resides in the N-terminal region of TNFR1 covering parts of CRD1 and CRD2. By site-directed mutagenesis, we identified Arg68 and His69 of TNFR1 as important residues for ATROSAB binding. ATROSAB inhibited binding of 125I-labeled TNF to HT1080 in the subnanomolar range. Furthermore, ATROSAB inhibited release of IL-6 and IL-8 from HeLa and HT1080 cells, respectively, induced by TNF or lymphotoxin alpha (LTα). Different from an agonistic antibody (Htr-9), which binds to a region close to the ATROSAB epitope but elicits strong TNFR1 activation, ATROSAB showed a negligible induction of IL-6 and IL-8 production over a broad concentration range. We further verified that ATROSAB, comprising mutations within the Fc region known to abrogate complement fixation and antibody-mediated cellular effector functions, indeed lacks binding activity for C1q, FcγRI (CD64), FcγRIIB (CD32b), and FcγRIII (CD16) disabling ADCC and CDC. Conlusions/Significance The data corroborate ATROSAB’s unique function as a TNFR1-selective antagonist efficiently blocking both TNF and LTα action. In agreement with recent studies of TNFR1 complex formation and activation, we suggest a model of the underlying mechanism of TNFR1 inhibition by ATROSAB.
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