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Turk A, Čeh E, Calin GA, Kunej T. Multiple omics levels of chronic lymphocytic leukemia. Cell Death Discov 2024; 10:293. [PMID: 38906881 PMCID: PMC11192936 DOI: 10.1038/s41420-024-02068-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 06/23/2024] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by the proliferation of functionally mature but incompetent B cells. It is the most prevalent type of leukemia in Western populations, accounting for approximately 25% of new leukemia cases. While recent advances, such as ibrutinib and venetoclax treatment have improved patient outlook, aggressive forms of CLL such as Richter transformation still pose a significant challenge. This discrepancy may be due to the heterogeneity of factors contributing to CLL development at multiple -omics levels. However, information on the omics of CLL is fragmented, hindering multi-omics-based research into potential treatment options. To address this, we aggregated and presented a selection of important aspects of various omics levels of the disease in this review. The purpose of the present literature analysis is to portray examples of CLL studies from different omics levels, including genomics, epigenomics, transcriptomics, epitranscriptomics, proteomics, epiproteomics, metabolomics, glycomics and lipidomics, as well as those identified by multi-omics approaches. The review includes the list of 102 CLL-associated genes with relevant genomics information. While single-omics studies yield substantial and useful data, they omit a significant level of complex biological interplay present in the disease. As multi-omics studies integrate several different layers of data, they may be better suited for complex diseases such as CLL and have thus far yielded promising results. Future multi-omics studies may assist clinicians in improved treatment choices based on CLL subtypes as well as allow the identification of novel biomarkers and targets for treatments.
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Grants
- R01 CA222007 NCI NIH HHS
- R01 GM122775 NIGMS NIH HHS
- P4-0220 Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)
- R01 CA182905 NCI NIH HHS
- P50 CA127001 NCI NIH HHS
- Dr. Calin is the Felix L. Haas Endowed Professor in Basic Science. Work in G.A.C.’s laboratory is supported by NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, NIGMS grant 1R01GM122775-01, DoD Idea Award W81XWH-21-1-0030, a Team DOD grant in Gastric Cancer W81XWH-21-1-0715, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a CLL Global Research Foundation 2019 grant, a CLL Global Research Foundation 2020 grant, a CLL Global Research Foundation 2022 grant, The G. Harold & Leila Y. Mathers Foundation, two grants from Torrey Coast Foundation, an Institutional Research Grant and Development Grant associated with the Brain SPORE 2P50CA127001.
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Affiliation(s)
- Aleksander Turk
- Clinical Institute of Genomic Medicine, University Clinical Centre Ljubljana, Ljubljana, Slovenia
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Eva Čeh
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - George A Calin
- Department of Translational Molecular Pathology, Division of Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX, 77030, USA.
| | - Tanja Kunej
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
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Ramirez-Perez S, Vekariya R, Gautam S, Reyes-Perez IV, Drissi H, Bhattaram P. MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients. Arthritis Res Ther 2023; 25:180. [PMID: 37749630 PMCID: PMC10519089 DOI: 10.1186/s13075-023-03145-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 08/23/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Dimerization of the myeloid differentiation primary response 88 protein (MyD88) plays a pivotal role in the exacerbated response to innate immunity-dependent signaling in rheumatoid arthritis (RA). ST2825 is a highly specific inhibitor of MyD88 dimerization, previously shown to inhibit the pro-inflammatory gene expression in peripheral blood mononuclear cells from RA patients (RA PBMC). In this study, we elucidated the effect of disrupting MyD88 dimerization by ST2825 on the pathological properties of synovial fibroblasts from RA patients (RA SFs). METHODS RA SFs were treated with varying concentrations of ST2825 in the presence or absence of bacterial lipopolysaccharides (LPS) to activate innate immunity-dependent TLR signaling. The DNA content of the RA SFs was quantified by imaging cytometry to investigate the effect of ST2825 on different phases of the cell cycle and apoptosis. RNA-seq was used to assess the global response of the RA SF toward ST2825. The invasiveness of RA SFs in Matrigel matrices was measured in organoid cultures. SFs from osteoarthritis (OA SFs) patients and healthy dermal fibroblasts were used as controls. RESULTS ST2825 reduced the proliferation of SFs by arresting the cells in the G0/G1 phase of the cell cycle. In support of this finding, transcriptomic analysis by RNA-seq showed that ST2825 may have induced cell cycle arrest by primarily inhibiting the expression of critical cell cycle regulators Cyclin E2 and members of the E2F family transcription factors. Concurrently, ST2825 also downregulated the genes encoding for pain, inflammation, and joint catabolism mediators while upregulating the genes required for the translocation of nuclear proteins into the mitochondria and members of the mitochondrial respiratory complex 1. Finally, we demonstrated that ST2825 inhibited the invasiveness of RA SFs, by showing decreased migration of LPS-treated RA SFs in spheroid cultures. CONCLUSIONS The pathological properties of the RA SFs, in terms of their aberrant proliferation, increased invasiveness, upregulation of pain and inflammation mediators, and disruption of mitochondrial homeostasis, were attenuated by ST2825 treatment. Taken together with the previously reported anti-inflammatory effects of ST2825 in RA PBMC, this study strongly suggests that targeting MyD88 dimerization could mitigate both systemic and synovial pathologies in a variety of inflammatory arthritic diseases.
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Affiliation(s)
- Sergio Ramirez-Perez
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA, 30329, USA.
| | - Rushi Vekariya
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA, 30329, USA
| | - Surabhi Gautam
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA, 30329, USA
| | - Itzel Viridiana Reyes-Perez
- Department of Molecular Biology and Genomics, University Center for Health Science, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Hicham Drissi
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA, 30329, USA
- Atlanta VA Medical Center, Decatur, GA, 30033, USA
| | - Pallavi Bhattaram
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA, 30329, USA.
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Ramirez-Perez S, Oregon-Romero E, Reyes-Perez IV, Bhattaram P. Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients. Front Pharmacol 2021; 12:800220. [PMID: 35002734 PMCID: PMC8735861 DOI: 10.3389/fphar.2021.800220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
MyD88-dependent intracellular signalling cascades and subsequently NF-kappaB-mediated transcription lead to the dynamic inflammatory processes underlying the pathogenesis of rheumatoid arthritis (RA) and related autoimmune diseases. This study aimed to identify the effect of the MyD88 dimerization inhibitor, ST2825, as a modulator of pathogenic gene expression signatures and systemic inflammation in disease-modifying antirheumatic drugs (DMARDs)-naïve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β. The transcriptional profiles of ST2825-treated PBMC were analyzed to identify its therapeutic potential. Ingenuity Pathway Analysis was implemented to identify downregulated pathogenic processes. Our analysis revealed 631 differentially expressed genes between DMARDs-naïve RA patients before and after ST2825 treatment. ST2825-treated RA PBMC exhibited a gene expression signature similar to that of healthy controls PBMC by downregulating the expression of proinflammatory cytokines, chemokines and matrix metalloproteases. In addition, B cell receptor, IL-17 and IL-15 signalling were critically downregulated pathways by ST2825. Furthermore, we identified eight genes (MMP9, CXCL9, MZB1, FUT7, TGM2, IGLV1-51, LINC01010, and CDK1) involved in pathogenic processes that ST2825 can potentially inhibit in distinct cell types within the RA synovium. Overall, our findings indicate that targeting MyD88 effectively downregulates systemic inflammatory mediators and modulates the pathogenic processes in PBMC from DMARDs-naïve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.
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Affiliation(s)
- Sergio Ramirez-Perez
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, United States
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States
| | - Edith Oregon-Romero
- Biomedical Sciences Research Institute (IICB), University of Guadalajara, Guadalajara, Mexico
| | | | - Pallavi Bhattaram
- Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA, United States
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States
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Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor. Molecules 2020; 25:molecules25184322. [PMID: 32967164 PMCID: PMC7570868 DOI: 10.3390/molecules25184322] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/16/2020] [Accepted: 09/18/2020] [Indexed: 12/31/2022] Open
Abstract
The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.
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Chen L, Zheng L, Chen P, Liang G. Myeloid Differentiation Primary Response Protein 88 (MyD88): The Central Hub of TLR/IL-1R Signaling. J Med Chem 2020; 63:13316-13329. [DOI: 10.1021/acs.jmedchem.0c00884] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Lingfeng Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Lulu Zheng
- Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310000, China
| | - Pengqin Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
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Chen L, Chen H, Chen P, Zhang W, Wu C, Sun C, Luo W, Zheng L, Liu Z, Liang G. Development of 2-amino-4-phenylthiazole analogues to disrupt myeloid differentiation factor 88 and prevent inflammatory responses in acute lung injury. Eur J Med Chem 2019; 161:22-38. [PMID: 30342423 DOI: 10.1016/j.ejmech.2018.09.068] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/11/2018] [Accepted: 09/26/2018] [Indexed: 11/16/2022]
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Ma B, Yang Y, Li Z, Zhao D, Zhang W, Jiang Y, Xue D. Modular bioinformatics analysis demonstrates that a Toll‑like receptor signaling pathway is involved in the regulation of macrophage polarization. Mol Med Rep 2018; 18:4313-4320. [PMID: 30221738 PMCID: PMC6172368 DOI: 10.3892/mmr.2018.9486] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 08/24/2018] [Indexed: 12/23/2022] Open
Abstract
In recent years, an increasing number of studies on the roles of macrophages in tumors, immune responses and metabolism have been published, in which macrophage polarization has been an extensively discussed topic. In the present study, differentially expressed genes in various types of macrophages were analyzed using the Gene Expression Omnibus database. Cluster analysis of differentially expressed genes was conducted, and a protein-protein interaction (PPI) network was constructed. Finally, modular analysis and functional enrichment analysis revealed that a Toll-like receptor (TLR) signaling pathway is involved in the regulation of macrophage polarization. Furthermore, the high-degree proteins in the PPI network that are involved in the molecular regulation of macrophage polarization are closely associated with proteins of the TLR signaling pathway. These results suggested that the TLR signaling pathways may be a principal direction of future research on the regulation of macrophage polarization.
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Affiliation(s)
- Biao Ma
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yang Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhituo Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dali Zhao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yanfeng Jiang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Sun RF, Yu QQ, Young KH. Critically dysregulated signaling pathways and clinical utility of the pathway biomarkers in lymphoid malignancies. Chronic Dis Transl Med 2018; 4:29-44. [PMID: 29756121 PMCID: PMC5938286 DOI: 10.1016/j.cdtm.2018.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Indexed: 12/15/2022] Open
Abstract
Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the “driver” oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Nevertheless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.
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Affiliation(s)
- Rui-Fang Sun
- Tumor Biobank, Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030013, China
| | - Qian-Qian Yu
- Tumor Biobank, Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030013, China
| | - Ken H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA
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Suckling CJ, Alam S, Olson MA, Saikh KU, Harnett MM, Harnett W. Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling. Sci Rep 2018; 8:2123. [PMID: 29391452 PMCID: PMC5794923 DOI: 10.1038/s41598-018-20388-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/15/2018] [Indexed: 01/01/2023] Open
Abstract
ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is anti-inflammatory by virtue of covalently attached phosphorylcholine. Previously we have reported that drug-like Small Molecule Analogues (SMAs) of its phosphorylcholine moiety can mimic ES-62 in protecting against disease development in certain mouse models of autoimmune and allergic conditions, due to them causing partial degradation of the TLR/IL-1R adaptor MyD88. We have now taken a molecular modelling approach to investigating the mechanism underlying this effect and this predicts that the SMAs interact directly with the MyD88 TIR domain. Further support for this is provided by assay of LPS-induced MyD88/NF-κB-driven secreted alkaline phosphatase (SEAP) reporter activity in commercially-available stably transfected (TLR4-MD2-NF-κB-SEAP) HEK293 cells, as SMA12b-mediated inhibition of such SEAP activity is blocked by its pre-incubation with recombinant MyD88-TIR domain. Direct binding of SMA12b to the TIR domain is also shown to inhibit homo-dimerization of the adaptor, an event that can explain the observed degradation of the adaptor and inhibition of subsequent downstream signalling. Thus, these new data identify initial events by which drug-like ES-62 SMAs, which we also demonstrate are able to inhibit cytokine production by human cells, homeostatically maintain "safe" levels of MyD88 signalling.
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Affiliation(s)
- Colin J Suckling
- WestCHEM Research School, Department of Pure & Applied Chemistry, University of Strathclyde, Glasgow, UK
| | - Shahabuddin Alam
- Department of Immunology, Molecular and Translational Sciences Division, Army Medical Research Institute of Infectious Diseases, Frederick, MD, 21702, USA
| | - Mark A Olson
- Department of Cell Biology and Biochemistry, Molecular and Translational Sciences Division, Army Medical Research Institute of Infectious Diseases, Frederick, MD, 21702, USA
| | - Kamal U Saikh
- Department of Immunology, Molecular and Translational Sciences Division, Army Medical Research Institute of Infectious Diseases, Frederick, MD, 21702, USA
| | - Margaret M Harnett
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
| | - William Harnett
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
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Yan H, Zhang D, Wei Y, Ni H, Liang W, Zhang H, Hao S, Jin W, Li K, Hang CH. Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage. Sci Rep 2017; 7:15797. [PMID: 29150630 PMCID: PMC5693947 DOI: 10.1038/s41598-017-16124-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 11/03/2017] [Indexed: 12/15/2022] Open
Abstract
Accumulating of evidence suggests that activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking pro-inflammatory and pro-apoptotic signaling. Myeloid differentiation primary response protein 88 (MyD88) is an endogenous adaptor protein in the toll-like receptors (TLRs) and interleukin (IL) -1β family signaling pathways and acts as a bottle neck in the NF-κB and MAPK pathways. Here, we used ST2825, a selective inhibitor of MyD88, to clarify whether inhibiting MyD88 could provide neuroprotection in EBI following SAH. Our results showed that the expression of MyD88 was markedly increased at 24 h post SAH. Intracerebroventricular injection of ST2825 significantly reduced the expression of MyD88 at 24 h post SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that ST2825 inhibited SAH-induced phosphorylation of TAK1, p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Further, ST2825 administration diminished the SAH-induced inflammatory response and apoptosis. As a result, SAH-induced EBI was alleviated and neurological deficits caused by SAH were reversed. Our findings suggest that MyD88 inhibition confers marked neuroprotection against EBI following SAH. Therefore, MyD88 might be a promising new molecular target for the treatment of SAH.
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Affiliation(s)
- Huiying Yan
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Dingding Zhang
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Yongxiang Wei
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Hongbin Ni
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Weibang Liang
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Huasheng Zhang
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Shuangying Hao
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China
| | - Wei Jin
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China.
| | - Kuanyu Li
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
| | - Chun-Hua Hang
- Department of Neurosurgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China.
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Amin AD, Peters TL, Li L, Rajan SS, Choudhari R, Puvvada SD, Schatz JH. Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud 2017; 3:a001719. [PMID: 28487884 PMCID: PMC5411687 DOI: 10.1101/mcs.a001719] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.
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Affiliation(s)
- Amit Dipak Amin
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Tara L Peters
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Lingxiao Li
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Soumya Sundara Rajan
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Ramesh Choudhari
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Soham D Puvvada
- Department of Medicine, Division of Hematology-Oncology, University of Arizona Comprehensive Cancer Center, Tucson, Arizona 85719, USA
| | - Jonathan H Schatz
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
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Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88. Sci Rep 2017; 7:1009. [PMID: 28432355 PMCID: PMC5430896 DOI: 10.1038/s41598-017-01246-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/23/2017] [Indexed: 11/09/2022] Open
Abstract
Autophagy, the processes of delivery of intracellular components to lysosomes, regulates induction of inflammation. Inducible macroautophagy degrades inflammasomes and dysfunctional mitochondria to downregulate inflammatory signals. Nonetheless, the effects of constitutive basal autophagy on inflammatory signals are largely unknown. Here, we report a previously unknown effect of basal autophagy. Lysosomal inhibition induced weak inflammatory signals in the absence of a cellular stimulus and in the presence of a nutrient supply, and their induction was impaired by MyD88 deficiency. During lysosomal inhibition, MyD88 was accumulated, and overabundant MyD88 autoactivated downstream signaling or enhanced TLR/IL-1R-mediated signaling. MyD88 is probably degraded via basal microautophagy because macroautophagy inhibitors, ATG5 deficiency, and an activator of chaperone-mediated autophagy did not affect MyD88. Analysis using a chimeric protein whose monomerization/dimerization can be switched revealed that monomeric MyD88 is susceptible to degradation. Immunoprecipitation of monomeric MyD88 revealed its interaction with TRAF6. In TRAF6-deficient cells, degradation of basal MyD88 was enhanced, suggesting that TRAF6 participates in protection from basal autophagy. Thus, basal autophagy lowers monomeric MyD88 expression, and thereby autoactivation of inflammatory signals is prevented. Given that impairment of lysosomes occurs in various settings, our results provide novel insights into the etiology of inflammatory signals that affect consequences of inflammation.
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Sun R, Wang J, Young KH. Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies. Crit Rev Oncog 2017; 22:527-557. [PMID: 29604930 PMCID: PMC5961736 DOI: 10.1615/critrevoncog.2017020816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lymphoma is characterized by heterogeneous biology, pathologic features, and clinical outcome. This has been proven by accumulating pathologic and molecular evidence attributed to underlying aberrant alterations at genetic, epigenetic, transcriptional, protein, microenvironmental levels, and dysregulated oncogenic signaling pathways. In the era of precision medicine, targeting oncogenic pathways to design drugs and to optimize treatment regimens for the lymphoma patients is feasible and clinically significant. As such, further understanding of the biology and the mechanisms behind lymphoma development and identification of oncogenic pathway activation and pathway-based biomarkers to better design precise therapies are challenging but hopeful. Furthermore, pathway-based targeted therapies in combination with traditional chemotherapy, single specific targeted antibody therapy, and immunotherapy might raise the hope for the patients with lymphoma, especially for relapsed and refractory lymphoma patients.
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Affiliation(s)
- Ruifang Sun
- Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
- Tumor Biobank, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Jinfen Wang
- Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Ken H. Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX, USA
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Paulus A, Ailawadhi S, Chanan-Khan A. Novel therapeutic targets in Waldenstrom macroglobulinemia. Best Pract Res Clin Haematol 2016; 29:216-228. [PMID: 27825468 DOI: 10.1016/j.beha.2016.08.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 08/30/2016] [Indexed: 01/04/2023]
Abstract
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA. New drugs for established targets are also discussed. Lastly, we spotlight 3 highly innovative WM-specific therapies: MYD88 peptide inhibitors, MYD88L265P-directed immune activation and CD19-directed chimeric antigen receptor T-cell therapy, which are in various stages of development. Indeed, treatment of WM is poised to undergo a paradigm shift in the coming years towards highly disease-driven and more personalized therapeutic modalities with curative intent.
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Affiliation(s)
- Aneel Paulus
- Mayo Clinic Jacksonville, Department of Cancer Biology and Division of Hematology and Oncology, United States.
| | - Sikander Ailawadhi
- Mayo Clinic Jacksonville, Division of Hematology and Oncology, United States.
| | - Asher Chanan-Khan
- Mayo Clinic Jacksonville, Division of Hematology and Oncology, United States.
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15
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Patent highlights: December 2015-January 2016. Pharm Pat Anal 2016; 5:147-53. [PMID: 27088860 DOI: 10.4155/ppa-2016-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.
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16
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Feng Z, Wang Z, Yang M, Zhou L, Bao Y. Polysaccharopeptide exerts immunoregulatory effects via MyD88-dependent signaling pathway. Int J Biol Macromol 2016; 82:201-7. [DOI: 10.1016/j.ijbiomac.2015.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 10/15/2015] [Accepted: 11/02/2015] [Indexed: 10/22/2022]
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17
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Huang L, Liu Q, Zhang L, Zhang Q, Hu L, Li C, Wang S, Li J, Zhang Y, Yu H, Wang Y, Zhong Z, Xiong T, Xia X, Wang X, Yu L, Deng G, Cai X, Cui S, Weng C. Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK. J Biol Chem 2015; 290:27618-32. [PMID: 26363073 PMCID: PMC4646013 DOI: 10.1074/jbc.m115.660761] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/24/2015] [Indexed: 12/24/2022] Open
Abstract
TRAF family member-associated NF-κB activator (TANK) is a negative regulator of canonical NF-κB signaling in the Toll-like receptor- and B-cell receptor-mediated signaling pathways. However, functions of TANK in viral infection-mediated NF-κB activation remain unclear. Here, we reported that TANK was cleaved by encephalomyocarditis virus 3C at the 197 and 291 glutamine residues, which depends on its cysteine protease activity. In addition, encephalomyocarditis virus 3C impaired the ability of TANK to inhibit TRAF6-mediated NF-κB signaling. Interestingly, we found that several viral proteases encoded by the foot and mouth disease virus, porcine reproductive and respiratory syndrome virus, and equine arteritis virus also cleaved TANK. Our results suggest that TANK is a novel target of some viral proteases, indicating that some positive RNA viruses have evolved to utilize their major proteases to regulate NF-κB activation.
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Affiliation(s)
- Li Huang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Qinfang Liu
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Lijie Zhang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Quan Zhang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001, the College of Life Sciences, Yangtze University, Jingzhou 434100
| | - Liang Hu
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Changyao Li
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Shengnan Wang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Jiangnan Li
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Yuanfeng Zhang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Huibin Yu
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Yan Wang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001, the Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650093, and
| | - Zhaohua Zhong
- the Department of Microbiology, Harbin Medical University, Harbin 150081, China
| | - Tao Xiong
- the College of Life Sciences, Yangtze University, Jingzhou 434100
| | - Xueshan Xia
- the Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650093, and
| | - Xiaojun Wang
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Li Yu
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Guohua Deng
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Xuehui Cai
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001
| | - Shangjin Cui
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001,
| | - Changjiang Weng
- From the State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001,
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Bohers E, Mareschal S, Bertrand P, Viailly PJ, Dubois S, Maingonnat C, Ruminy P, Tilly H, Jardin F. Activating somatic mutations in diffuse large B-cell lymphomas: lessons from next generation sequencing and key elements in the precision medicine era. Leuk Lymphoma 2014; 56:1213-22. [DOI: 10.3109/10428194.2014.941836] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Gebauer N, Bernard V, Thorns C, Feller AC, Merz H. Oncogenic MYD88 mutations are rare events in double-hit B-cell lymphomas. Acta Haematol 2014; 133:113-5. [PMID: 25247317 DOI: 10.1159/000358914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 01/20/2014] [Indexed: 11/19/2022]
Affiliation(s)
- Niklas Gebauer
- Reference Center for Lymph Node Pathology and Hematopathology, Department of Pathology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
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20
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Gebauer N, Bernard V, Röhner C, Krokowski M, Merz H, Feller AC, Thorns C. Pyrosequencing as a fast and reliable method in detecting the MYD88 p.L265P mutation in decalcified formalin-fixed and paraffin-embedded tissues. Ann Lab Med 2014; 34:170-3. [PMID: 24624358 PMCID: PMC3948835 DOI: 10.3343/alm.2014.34.2.170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/25/2013] [Accepted: 12/17/2013] [Indexed: 11/19/2022] Open
Affiliation(s)
- Niklas Gebauer
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Veronica Bernard
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Claudia Röhner
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Manuela Krokowski
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Hartmut Merz
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Alfred C Feller
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
| | - Christoph Thorns
- Department of Pathology, Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Luebeck, Germany
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21
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Calil IL, Zarpelon AC, Guerrero ATG, Alves-Filho JC, Ferreira SH, Cunha FQ, Cunha TM, Verri WA. Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw. PLoS One 2014; 9:e90013. [PMID: 24595131 PMCID: PMC3940714 DOI: 10.1371/journal.pone.0090013] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 01/29/2014] [Indexed: 01/18/2023] Open
Abstract
Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-α, KC/CXCL1 and IL-1β expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1β release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-α release that in turn mediates rises in KC/CXCL1 and IL-1β expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine.
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Affiliation(s)
- Igor L. Calil
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Ana C. Zarpelon
- Departamento de Patologia, Centro de Ciências Biologicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | | | - Jose C. Alves-Filho
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Sergio H. Ferreira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Fernando Q. Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Thiago M. Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
- * E-mail: (WAV); (TMC)
| | - Waldiceu A. Verri
- Departamento de Patologia, Centro de Ciências Biologicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
- * E-mail: (WAV); (TMC)
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22
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Aravalli RN. Role of innate immunity in the development of hepatocellular carcinoma. World J Gastroenterol 2013; 19:7500-7514. [PMID: 24282342 PMCID: PMC3837249 DOI: 10.3748/wjg.v19.i43.7500] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 09/29/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. It is caused by a variety of risk factors, most common ones being infection with hepatitis viruses, alcohol, and obesity. HCC often develops in the background of underlying cirrhosis, and even though a number of interventional treatment methods are currently in use, recurrence is fairly common among patients who have had a resection. Therefore, whole liver transplantation remains the most practical treatment option for HCC. Due to the growing incidence of HCC, intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer. In recent years, it has become clear that innate immunity plays a critical role in the development of a number of liver diseases, including HCC. In particular, the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of pro-inflammatory cytokines and chemokines, and could cause acute inflammation in the liver. In this review, the current knowledge on the role of innate immune responses in the development and progression of HCC is examined, and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.
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23
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Loiarro M, Volpe E, Ruggiero V, Gallo G, Furlan R, Maiorino C, Battistini L, Sette C. Mutational analysis identifies residues crucial for homodimerization of myeloid differentiation factor 88 (MyD88) and for its function in immune cells. J Biol Chem 2013; 288:30210-30222. [PMID: 24019529 PMCID: PMC3798488 DOI: 10.1074/jbc.m113.490946] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/27/2013] [Indexed: 01/07/2023] Open
Abstract
Myeloid differentiation factor 88 (MyD88) is an adaptor protein that transduces intracellular signaling pathways evoked by the Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 is composed of an N-terminal death domain (DD) and a C-terminal Toll/IL-1 receptor (TIR) domain, separated by a short region. Upon ligand binding, TLR/IL-1Rs hetero- or homodimerize and recruit MyD88 through their respective TIR domains. Then, MyD88 oligomerizes via its DD and TIR domain and interacts with the interleukin-1 receptor-associated kinases (IRAKs) to form the Myddosome complex. We performed site-directed mutagenesis of conserved residues that are located in exposed regions of the MyD88-TIR domain and analyzed the effect of the mutations on MyD88 signaling. Our studies revealed that mutation of Glu(183), Ser(244), and Arg(288) impaired homodimerization of the MyD88-TIR domain, recruitment of IRAKs, and activation of NF-κB. Moreover, overexpression of two green fluorescent protein (GFP)-tagged MyD88 mini-proteins (GFP-MyD88151-189 and GFP-MyD88168-189), comprising the Glu(183) residue, recapitulated these effects. Importantly, expression of these dominant negative MyD88 mini-proteins competed with the function of endogenous MyD88 and interfered with TLR2/4-mediated responses in a human monocytic cell line (THP-1) and in human primary monocyte-derived dendritic cells. Thus, our studies identify novel residues of the TIR domain that are crucially involved in MyD88 homodimerization and TLR signaling in immune cells.
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Affiliation(s)
- Maria Loiarro
- From the Department of Biomedicine and Prevention, University of Rome "Tor Vergata", 00133 Rome, Italy,; the Laboratory of Neuroembryology and
| | - Elisabetta Volpe
- Laboratory of Neuroimmunology, Santa Lucia Foundation, 00143 Rome, Italy
| | - Vito Ruggiero
- the Research & Development Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy, and
| | - Grazia Gallo
- the Research & Development Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy, and
| | - Roberto Furlan
- the Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Chiara Maiorino
- the Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Luca Battistini
- Laboratory of Neuroimmunology, Santa Lucia Foundation, 00143 Rome, Italy
| | - Claudio Sette
- From the Department of Biomedicine and Prevention, University of Rome "Tor Vergata", 00133 Rome, Italy,; the Laboratory of Neuroembryology and.
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