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Kim KC, Jeong GH, Bang CH, Lee JH. Cannabichromene as a Novel Inhibitor of Th2 Cytokine and JAK/STAT Pathway Activation in Atopic Dermatitis Models. Int J Mol Sci 2024; 25:13539. [PMID: 39769302 PMCID: PMC11677870 DOI: 10.3390/ijms252413539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/10/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Cannabichromene (CBC) is one of the main cannabinoids found in the cannabis plant, and although less well known than tetrahydrocannabinol (THC) and cannabidiol (CBD), it is gaining attention for its potential therapeutic benefits. To date, CBC's known mechanisms of action include anti-inflammatory, analgesic, antidepressant, antimicrobial, neuroprotective, and anti-acne effects through TRP channel activation and the inhibition of inflammatory pathways, suggesting that it may have therapeutic potential in the treatment of inflammatory skin diseases, such as atopic dermatitis (AD), but its exact mechanism of action remains unclear. Therefore, in this study, we investigated the effects of CBC on Th2 cytokines along with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in AD pathogenesis. We used a 2,4-Dinitrochlorobenzene (DNCB)-induced BALB/c mouse model to topically administer CBC (0.1 mg/kg or 1 mg/kg). The results showed that skin lesion severity, ear thickness, epithelial thickness of dorsal and ear skin, and mast cell infiltration were significantly reduced in the 0.1 mg/kg CBC-treated group compared with the DNCB-treated group (p < 0.001). In addition, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed a significant decrease in the mRNA expression of Th2 cytokines (TSLP, IL-4, IL-13) and inflammatory mediators (IFN-γ, IL-1β, IL-6, IL-17, IL-18, and IL-33) (p < 0.05). Western blot analysis also revealed a significant decrease in JAK1, JAK2, STAT1, STAT2, STAT3, and STAT6 protein expression (p < 0.05). These results suggest that CBC is a promising candidate for the treatment of AD and demonstrates the potential to alleviate AD symptoms by suppressing the Th2 immune response.
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Affiliation(s)
- Ki Chan Kim
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (K.C.K.); (G.H.J.); (C.H.B.)
| | - Ga Hee Jeong
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (K.C.K.); (G.H.J.); (C.H.B.)
| | - Chul Hwan Bang
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (K.C.K.); (G.H.J.); (C.H.B.)
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
| | - Ji Hyun Lee
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (K.C.K.); (G.H.J.); (C.H.B.)
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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Han XY, Han YR, Xu HY, Hu YW, Yan XY, Du GH, She ZF, Xiao B. The anti-rheumatoid arthritic activity of Artemisia ordosica Krasch. (traditional Chinese/Mongolian medicine) extract in collagen-induced arthritis in rats. J Pharm Pharmacol 2024; 76:1463-1473. [PMID: 39066578 DOI: 10.1093/jpp/rgae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 07/06/2024] [Indexed: 07/28/2024]
Abstract
OBJECTIVES Rheumatoid arthritis (RA) seriously affects the daily life of people. The whole plant of Artemisia ordosica Krasch. (AOK) has been used in folk medicine. This study aimed to investigate the in vivo anti-RA effects of AOK extract (AOKE) on collagen-induced arthritis in rats. METHODS AOKE (400, 200, or 100 mg/kg) was administered orally to animals for 30 days. Body weight, paw swelling, arthritis index, thymus, and spleen indices, and pathological changes were assessed for effects of AOKE on RA. Furthermore, the inflammatory cytokines in rat serum were detected. In addition, the expressions of STAT3, Caspase-3, Galectin-3, and S100A9 in synovial tissue were researched using immunohistochemistry. KEY FINDINGS The AOKE significantly reduced the arthritis indices, paw swelling, spleen, and thymus indices. Meanwhile, AOKE (400 mg/kg) decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17A, and increased the level of IL-10 in rat serum. Histopathological examination showed that AOKE reduced inflammatory cell infiltration and cartilage erosion. Then, AOKE decreased the expressions of STAT3, Galectin-3, S100A9, and increased the expression of Caspase-3. CONCLUSION AOKE had interesting anti-RA activity in rats, which deserved further research for the development and clinical use of this medicinal resource.
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Affiliation(s)
- Xiao-Yan Han
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Ya-Ru Han
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Hao-Yu Xu
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Ya-Wei Hu
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Xiao-Yan Yan
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Guan-Hua Du
- Beijing Key Laboratory of Drug Target Identification, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Zhan-Fei She
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
| | - Bin Xiao
- General Clinical Research Center, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, Ordos 017000, China
- Beijing Key Laboratory of Drug Target Identification, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
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Ghosh R, Bishayi B. Neutralization of TLR2 in combination with either TNF-α or IL-1β antibody reduces the severity of septic arthritis through STAT3/mTOR signalling in lymphocytes. Cell Immunol 2024; 405-406:104878. [PMID: 39312873 DOI: 10.1016/j.cellimm.2024.104878] [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: 07/06/2024] [Revised: 08/23/2024] [Accepted: 09/13/2024] [Indexed: 09/25/2024]
Abstract
Staphylococcus aureus induced Septic arthritis is considered a medical concern. S.aureus binds TLR2 to induce an array of inflammatory responses. Generation of pro-inflammatory cytokines induces T cell responses and control Th17/Treg cell balance. Regulation of T cell-mediated immunity in response to inflammation is significantly influenced by mTOR. Presence of elevated TNF-α, IL-1β decreases Treg cell activity through STAT3/mTOR, promoting proliferation of T cells towards Th17 cells. Therefore, we postulated, neutralizing TLR2 with either TNF-α or IL-1β in combination could be useful in modifying Th17/Treg cell ratio in order to treat septic arthritis by suppressing expression of mTOR/STAT3. To date, no studies have reported effects of neutralization of TLR2 along with either TNF-α or IL-1β on amelioration of arthritis correlating with mTOR/STAT3 expression. Contribution of T lymphocytes collected from blood, spleen, synovial tissues, their derived cytokines IFN-γ, IL-6, IL-17, TGF-β, IL-10 were noted. Expression of TLR2, TNFR1, TNFR2, NF-κB along with mTOR/STAT3 also recorded. Neutralization of TLR2 along with TNF-α and IL-1β were able to shift Th17 cells into immunosuppressive Treg cells. Furthermore,elevated expression of IL-10, TNFR2 and demoted expression of mTOR/ STAT3 along with NF-κB in lymphocytes confirms its role in resolution of arthritis. It was also effective in reducing oxidative stress via increasing expression of the antioxidant enzymes. As a result, it can be inferred that Treg-derived IL-10, which may mitigate inflammatory effects of septic arthritis by influencing the mTOR/STAT3 interaction in lymphocytes, may be selected as a different therapeutic strategy for reducing the impact of septic arthritis.
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Affiliation(s)
- Rituparna Ghosh
- Department of Physiology, Immunology laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
| | - Biswadev Bishayi
- Department of Physiology, Immunology laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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Tao Y, Liu J, Li M, Wang H, Fan G, Xie X, Fu X, Su J. Abelmoschus manihot (L.) medik. seeds alleviate rheumatoid arthritis by modulating JAK2/STAT3 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 325:117641. [PMID: 38151179 DOI: 10.1016/j.jep.2023.117641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 12/29/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Abelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown. AIM OF THE STUDY This research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA. MATERIALS AND METHODS The ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1β, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats' synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking. RESULT In the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1β, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4'-methoxy-bavachromanol, and quercetin. CONCLUSION According to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.
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Affiliation(s)
- Yiwen Tao
- School of Ethnic Medicine and Meishan Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jia Liu
- School of Ethnic Medicine and Meishan Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Mengjia Li
- School of Ethnic Medicine and Meishan Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Hongling Wang
- Pingshan County Hospital of Chinese Medicine, Yibin, Sichuan, China
| | - Gang Fan
- School of Ethnic Medicine and Meishan Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaolong Xie
- School of Ethnic Medicine and Meishan Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Xing Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Jinsong Su
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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Zhang FF, Hao Y, Zhang KX, Yang JJ, Zhao ZQ, Liu HJ, Li JT. Interplay between mesenchymal stem cells and macrophages: Promoting bone tissue repair. World J Stem Cells 2024; 16:375-388. [PMID: 38690513 PMCID: PMC11056637 DOI: 10.4252/wjsc.v16.i4.375] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.
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Affiliation(s)
- Fei-Fan Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yang Hao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Kuai-Xiang Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Jiang-Jia Yang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhi-Qiang Zhao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
| | - Hong-Jian Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ji-Tian Li
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
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Filipović M, Flegar D, Aničić S, Šisl D, Kelava T, Kovačić N, Šućur A, Grčević D. Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2 hi osteoclast progenitors. Front Immunol 2022; 13:994035. [PMID: 36591261 PMCID: PMC9797520 DOI: 10.3389/fimmu.2022.994035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction The existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior. Methods In order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation. Results A disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis. Conclusion Our approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.
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Affiliation(s)
- Maša Filipović
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Darja Flegar
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sara Aničić
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Dino Šisl
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Tomislav Kelava
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Nataša Kovačić
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alan Šućur
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
| | - Danka Grčević
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
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Du J, Zheng L, Chen S, Wang N, Pu X, Yu D, Yan H, Chen J, Wang D, Shen B, Li J, Pan S. NFIL3 and its immunoregulatory role in rheumatoid arthritis patients. Front Immunol 2022; 13:950144. [PMID: 36439145 PMCID: PMC9692021 DOI: 10.3389/fimmu.2022.950144] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 10/18/2022] [Indexed: 11/13/2022] Open
Abstract
Nuclear-factor, interleukin 3 regulated (NFIL3) is an immune regulator that plays an essential role in autoimmune diseases. However, the relationship between rheumatoid arthritis (RA) and NFIL3 remains largely unknown. In this study, we examined NFIL3 expression in RA patients and its potential molecular mechanisms in RA. Increased NFIL3 expression levels were identified in peripheral blood mononuclear cells (PBMCs) from 62 initially diagnosed RA patients and 75 healthy controls (HCs) by quantitative real-time PCR (qRT-PCR). No correlation between NFIL3 and disease activity was observed. In addition, NFIL3 expression was significantly upregulated in RA synovial tissues analyzed in the Gene Expression Omnibus (GEO) dataset (GSE89408). Then, we classified synovial tissues into NFIL3-high (≥75%) and NFIL3-low (≤25%) groups according to NFIL3 expression levels. Four hundred five differentially expressed genes (DEGs) between the NFIL3-high and NFIL3-low groups were screened out using the “limma” R package. Enrichment analysis showed that most of the enriched genes were primarily involved in the TNF signaling pathway via NFκB, IL-17 signaling pathway, and rheumatoid arthritis pathways. Then, 10 genes (IL6, IL1β, CXCL8, CCL2, PTGS2, MMP3, MMP1, FOS, SPP1, and ADIPOQ) were identified as hub genes, and most of them play a key role in RA. Positive correlations between the hub genes and NFIL3 were revealed by qRT-PCR in RA PBMCs. An NFIL3-related protein–protein interaction (PPI) network was constructed using the STRING database, and four clusters (mainly participating in the inflammatory response, lipid metabolism process, extracellular matrix organization, and circadian rhythm) were constructed with MCODE in Cytoscape. Furthermore, 29 DEGs overlapped with RA-related genes from the RADB database and were mainly enriched in IL-17 signaling pathways. Thus, our study revealed the elevated expression of NFIL3 in both RA peripheral blood and synovial tissues, and the high expression of NFIL3 correlated with the abnormal inflammatory cytokines and inflammatory responses, which potentially contributed to RA progression.
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Affiliation(s)
- Juping Du
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Liyuan Zheng
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Shuaishuai Chen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Na Wang
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Xia Pu
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Die Yu
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Haixi Yan
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Jiaxi Chen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Donglian Wang
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Bo Shen
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
| | - Jun Li
- Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, China
- *Correspondence: Shaobiao Pan, ; Jun Li,
| | - Shaobiao Pan
- Department of Rheumatology and Immunology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- *Correspondence: Shaobiao Pan, ; Jun Li,
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Low-Dose Tacrolimus Promotes the Migration and Invasion and Nitric Oxide Production in the Human-Derived First Trimester Extravillous Trophoblast Cells In Vitro. Int J Mol Sci 2022; 23:ijms23158426. [PMID: 35955565 PMCID: PMC9369346 DOI: 10.3390/ijms23158426] [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: 08/16/2021] [Revised: 07/12/2022] [Accepted: 07/26/2022] [Indexed: 02/04/2023] Open
Abstract
Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p < 0.001) stimulate the migration and invasion of the HTR-8/SVneo cells, inducing their cytosolic/nuclear progesterone receptor expression and activation, and modulating their Nitric Oxide (NO) production. Moreover, tacrolimus abrogated the suppressive effect of the NOS inhibitor Nω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent.
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Li S, Zhou H, Xie M, Zhang Z, Gou J, Yang J, Tian C, Ma K, Wang CY, Lu Y, Li Q, Peng W, Xiang M. Regenerating islet-derived protein 3 gamma (Reg3g) ameliorates tacrolimus-induced pancreatic β-cell dysfunction in mice by restoring mitochondrial function. Br J Pharmacol 2022; 179:3078-3095. [PMID: 35060126 DOI: 10.1111/bph.15803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 12/29/2021] [Accepted: 12/30/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Tacrolimus a first-line medication used after transplantation can induce β-cell dysfunction, causing new-onset diabetes mellitus (NODM). Regenerating islet-derived protein 3 gamma (Reg3g), a member of the pancreatic regenerative gene family, has been reported to improve type 1 diabetes by promoting β-cell regeneration. We aim to investigate the role of Reg3g in reversing tacrolimus-induced β-cell dysfunction and NODM in mice. EXPERIMENTAL APPROACH Circulating REG3A (the human homologue of mouse Reg3g) in heart transplantation patients treated with tacrolimus was detected. The glucose-stimulated insulin secretion and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium, ATP production, oxygen consumption rate and mitochondrial morphology were investigated in β-cells. Additionally, effects of Reg3g on tacrolimus-induced NODM in mice were analysed. KEY RESULTS Circulating REG3A level in heart transplantation patients with NODM significantly decreased compared with those without diabetes. Tacrolimus down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored glucose-stimulated insulin secretion suppressed by tacrolimus in β-cells by improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, oxygen consumption rate and contributing to an intact mitochondrial morphology. Mechanistically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signalling pathway, leading to restoration of tacrolimus-induced mitochondrial impairment. Reg3g overexpression also effectively mitigated tacrolimus-induced NODM in mice. CONCLUSION AND IMPLICATIONS Reg3g can significantly ameliorate tacrolimus-induced β-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in tacrolimus-induced NODM and establish the novel role of Reg3g in reversing tacrolimus-induced β-cell dysfunction.
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Affiliation(s)
- Senlin Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyuan Xie
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zijun Zhang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Gou
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Yang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Tian
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Ma
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yi Lu
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Peng
- Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lee HG, Wheeler MA, Quintana FJ. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 2022; 21:339-358. [PMID: 35173313 PMCID: PMC9081171 DOI: 10.1038/s41573-022-00390-x] [Citation(s) in RCA: 297] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2022] [Indexed: 12/20/2022]
Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
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Affiliation(s)
- Hong-Gyun Lee
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael A Wheeler
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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11
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Cheng Y, Yu Y, Zhuang Q, Wang L, Zhan B, Du S, Liu Y, Huang J, Hao J, Zhu X. Bone erosion in inflammatory arthritis is attenuated by Trichinella spiralis through inhibiting M1 monocyte/macrophage polarization. iScience 2022; 25:103979. [PMID: 35281745 PMCID: PMC8914552 DOI: 10.1016/j.isci.2022.103979] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/19/2022] [Accepted: 02/18/2022] [Indexed: 12/23/2022] Open
Abstract
Helminths and helminth-derived products hold promise for treating joint bone erosion in rheumatoid arthritis (RA). However, the mechanisms of helminths ameliorating the osteoclastic bone destruction are incompletely understood. Here, we report that Trichinella spiralis infection or treatment with the excreted/secreted products of T. spiralis muscle larvae (MES) attenuated bone erosion and osteoclastogenesis in mice with collage-induced arthritis (CIA) through inhibiting M1 monocyte/macrophage polarization and the production of M1-related proinflammatory cytokines. In vitro, MES inhibited LPS-induced M1 macrophage activation while promoting IL-4-induced M2 macrophage polarization. Same effects of MES were also observed in monocytes derived from RA patients, wherein MES treatment suppressed LPS-induced M1 cytokine production. Moreover, MES treatment attenuated LPS and RANKL co-stimulated osteoclast differentiation from the RAW264.7 macrophages through inhibiting activation of the NF-κB rather than MAPK pathway. This study provides insight into the M1 subset as a potential target for helminths to alleviate osteoclastic bone destruction in RA.
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Affiliation(s)
- Yuli Cheng
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Yan Yu
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Qinghui Zhuang
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Lei Wang
- Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China
| | - Bin Zhan
- Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Suqin Du
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Yiqi Liu
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Jingjing Huang
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
| | - Junfeng Hao
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, PR China
| | - Xinping Zhu
- Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China
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Wang Z, Wei Y, Lei L, Zhong J, Shen Y, Tan J, Xia M, Wu Y, Sun W, Chen L. RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression. Connect Tissue Res 2021; 62:411-426. [PMID: 32370570 DOI: 10.1080/03008207.2020.1759562] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts.Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression.Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade.Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy-JAK2-STAT3 signaling pathway, thus affecting bone metabolism.
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Affiliation(s)
- Zhongxiu Wang
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yingming Wei
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lihong Lei
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiahui Zhong
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yeqi Shen
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingyi Tan
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mengjiao Xia
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanmin Wu
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilian Sun
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lili Chen
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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13
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Liu C, Zhao Q, Zhong L, Li Q, Li R, Li S, Li Y, Li N, Su J, Dhondrup W, Meng X, Zhang Y, Tu Y, Wang X. Tibetan medicine Ershiwuwei Lvxue Pill attenuates collagen-induced arthritis via inhibition of JAK2/STAT3 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113820. [PMID: 33465441 DOI: 10.1016/j.jep.2021.113820] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/18/2020] [Accepted: 01/11/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ershiwuwei Lvxue Pill (ELP, མགྲིན་མཚལ་ཉེར་ལྔ།), a traditional Tibetan medicine preparation, has been used hundreds of years for the clinical treatment of rheumatoid arthritis (RA) in the highland region of Tibet, China. However, the underlying mechanism of its therapeutic effect remains unclear. AIM OF THE STUDY The present study aimed to investigate the potential pharmacological mechanisms of anti-arthritic effect of ELP. MATERIALS AND METHODS The main chemical constituents of ELP were analyzed by ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS). Forty-eight male Wistar rats (220 ± 20 g) were randomly divided into six groups: normal group, collagen-induced arthritis (CIA) group, methotrexate group (1.05 mg/kg), ELP groups (115, 230 and 460 mg/kg). CIA rat models were assigned to evaluate the anti-RA activity of ELP by determining the paws swelling, arthritis score, organ coefficients of spleen and thymus, and histopathological analysis of knee joints of synovial tissues. The levels of TNF-α, IL-10, IL-6 and IL-17 in serum were measured by ELISA. In addition, mRNA and protein expression levels associated with JAK2/STAT3 signaling pathway in synovial tissues of CIA rats were detected by qRT-PCR, immunohistochemistry and Western blot analyses. RESULTS Fourteen main chemical constituents of ELP were quantitatively determined by UPLC-Q-TOF-MS analysis. Treatment with ELP reduced the paw swelling, arthritis score and organ coefficients of spleen and thymus. Histopathological examination revealed the protective effects of ELP on CIA rats with knee joint injury. The levels of serum pro-inflammatory cytokines (TNF-α, IL-6 and IL-17) were markedly reduced while the anti-inflammatory cytokine IL-10 was significantly increased with the treatment of ELP. Further investigations showed ELP down-regulated the mRNA and protein expression levels of Bcl-2, whereas up-regulated Bax, SOCS1 and SOCS3. Meanwhile, the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 proteins from synovial tissues were dramatically decreased with the treatment of ELP, whereas no changes of the mRNA and protein expression levels of JAK2 and STAT3 were observed. CONCLUSION These results indicated that ELP reduced the severity of arthritis and joint swelling, suggesting an antirheumatic effect on CIA rats. The possible mechanism is related to inhibiting inflammatory response and inducing apoptosis in synovial tissues by regulating JAK2/STAT3 signaling pathway. However, further in vivo and in vitro investigations are still needed to clarify the underlying mechanism of ELP in treating RA.
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Affiliation(s)
- Chuan Liu
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian Zhao
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lu Zhong
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qiuyue Li
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Rui Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shuang Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yangxin Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Ning Li
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jinsong Su
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Wüntrang Dhondrup
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xianli Meng
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yi Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; NMPA Key Laboratory for Quality Evaluation of Traditional Chinese Medicine (Traditional Chinese Patent Medicine), Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Ya Tu
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Development Research Center of Traditional Chinese Medicine, China Academy of Traditional Chinese Medicine, Beijing, 100700, China.
| | - Xiaobo Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Su J, Li Q, Liu J, Wang H, Li X, Wüntrang D, Liu C, Zhao Q, RuyuYao, Meng X, Zhang Y. Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 267:113514. [PMID: 33223115 DOI: 10.1016/j.jep.2020.113514] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). AIM OF THE STUDY This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. MATERIALS AND METHODS The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1β, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. CONCLUSION The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway.
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Affiliation(s)
- Jinsong Su
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Qiuyue Li
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Jia Liu
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Hongling Wang
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Xuanhao Li
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Dhondrup Wüntrang
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Chuan Liu
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Qian Zhao
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - RuyuYao
- Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100193,China
| | - Xianli Meng
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China
| | - Yi Zhang
- Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China.
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Lin JJ, Tao K, Gao N, Zeng H, Wang DL, Yang J, Weng J. Triptolide Inhibits Expression of Inflammatory Cytokines and Proliferation of Fibroblast-like Synoviocytes Induced by IL-6/sIL-6R-Mediated JAK2/STAT3 Signaling Pathway. Curr Med Sci 2021; 41:133-139. [PMID: 33582917 DOI: 10.1007/s11596-020-2302-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 09/23/2020] [Indexed: 12/16/2022]
Abstract
Triptolide, a component of the Chinese herb Tripterygium wilfordii Hook F, has been proved to be effective in the treatment of rheumatoid arthritis (RA). However, its underlying mechanisms on RA have not yet been well established. We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes (FLS) induced by the complex of interleukin-6 (IL-6) and the soluble form of the IL-6 receptor (sIL-6R). Furthermore, to clarify the underlying mechanisms, we treated FLS with the Janus-activated kinase 2 (JAK2) inhibitor/signal transducer and activator of transcription 3 (STAT3) activation blocker AZD1480. In this study, immunohistochemical staining was used to identify vimentin (+) and CD68 (-) in FLS. The FLS proliferation was measured by cell proliferation assay, and the cell cycles were analyzed by flow cytometry. Furthermore, ELISA was used to detect the expression of the inflammatory factors in culture solution. The expression levels of p-JAK2, JAK2, p-STAT3 and STAT3 were investigated through Western blotting analysis. The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines, including IL-6, interleukin-1β (IL-1β) and vascular endothelial growth factor (VEGF). Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3. The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway. It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.
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Affiliation(s)
- Jian-Jing Lin
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518000, China
- Arthritis Clinical and Research Center, Peking University People's Hospital, Beijing, 100044, China
| | - Ke Tao
- Arthritis Clinical and Research Center, Peking University People's Hospital, Beijing, 100044, China
| | - Nan Gao
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, 518000, China
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518000, China
| | - De-Li Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518000, China
| | - Jun Yang
- Department of Radiology, Peking University Shenzhen Hospital, Shenzhen, 518000, China.
| | - Jian Weng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518000, China.
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Santos MRG, Queiroz-Junior CM, Madeira MFM, Machado FS. Suppressors of cytokine signaling (SOCS) proteins in inflammatory bone disorders. Bone 2020; 140:115538. [PMID: 32730926 DOI: 10.1016/j.bone.2020.115538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/18/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
Suppressor of cytokine signaling (SOCS) proteins are significant regulators of cellular immune responses. Therefore, the role of SOCS in bone-inflammatory disorders, including arthritis and periodontitis, has been investigated in experimental and clinical conditions. Recent evidence shows that SOCS proteins are expressed in major bone-related cells, including osteoblasts, osteoclasts, chondrocytes and synoviocytes, although their direct role in these cells is not fully described. These signaling molecules, especially SOCS1, 2 and 3, were shown to play critical roles in the control of bone resorption associated to inflammation. This review focuses on the involvement of SOCS proteins in inflammatory bone remodeling, including their direct and indirect role in the control of osteoclast hyperactivation, during arthritis and periodontitis. The description of the roles of SOCS proteins in inflammatory bone diseases highlights the pathways involved in the pathophysiology of these conditions and, thus, may contribute to the development and improvement of potential therapeutic interventions.
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Affiliation(s)
- Mariana Rates Gonzaga Santos
- Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Celso M Queiroz-Junior
- Department of Morphology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Mila Fernandes Moreira Madeira
- Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil.
| | - Fabiana Simão Machado
- Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil; Program in Health Sciences: Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.
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Volzke J, Schultz D, Kordt M, Müller M, Bergmann W, Methling K, Kreikemeyer B, Müller-Hilke B. Inflammatory Joint Disease Is a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice. Front Immunol 2020; 11:579475. [PMID: 33117382 PMCID: PMC7576673 DOI: 10.3389/fimmu.2020.579475] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022] Open
Abstract
Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) – an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines (Ccl2, Cxcl2), inflammatory cytokines (Tnf, Il6), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling (Rankl) and cartilage integrity (Mmp13). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis.
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Affiliation(s)
- Johann Volzke
- Core Facility for Cell Sorting and Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Daniel Schultz
- Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Marcel Kordt
- Core Facility for Cell Sorting and Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Michael Müller
- Core Facility for Cell Sorting and Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Wendy Bergmann
- Core Facility for Cell Sorting and Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Karen Methling
- Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Rostock, Rostock, Germany
| | - Brigitte Müller-Hilke
- Core Facility for Cell Sorting and Cell Analysis, University Medical Center Rostock, Rostock, Germany
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Chen YJ, Wu JY, Leung WC, Liu YX, Fu XQ, Zhu JQ, Wu Y, Chou JY, Yin CL, Wang YP, Wang XQ, Bai JX, Wu ZZ, Yu ZL. An herbal formula inhibits STAT3 signaling and attenuates bone erosion in collagen-induced arthritis rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 76:153254. [PMID: 32531698 DOI: 10.1016/j.phymed.2020.153254] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 05/07/2020] [Accepted: 05/23/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Receptor activator of NF-κB ligand (RANKL) facilitates differentiation of osteoclast precursors into osteoclasts, resulting in bone erosion in rheumatoid arthritis (RA) patients. Fibroblast-like synoviocytes (FLS) are the main cells for producing RANKL. Signal transducer and activator of transcription 3 (STAT3) signaling is activated in FLS of RA patients (RA-FLS), which has been linked to RANKL production. A two-herb formula (RL) comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos is traditionally used for treating RA in China. We have found that a standardized ethanolic extract of RL (RLE for short) alleviates bone erosion in collagen-induced arthritis (CIA) rats. PURPOSE This study aimed to determine whether RLE inhibits RANKL production and osteoclastogenesis in cell and rat models, and to explore the involvement of the STAT3 pathway in this inhibition. STUDY DESIGN AND METHODS A CIA rat model, interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS and a co-culture system (IL-6/sIL-6R-stimulated RA-FLS/peripheral blood mononuclear cells) were used to evaluate the effects of RLE. Micro-computed tomography analysis was used to observe bone erosion in CIA rats. Tartrate-resistant acid phosphatase staining was used to evaluate osteoclastogenesis. Western blotting and ELISA assays were employed to examine protein levels. RT-qPCR was used to detect mRNA levels. STAT3-over-activated RA-FLS were used to investigate the involvement of STAT3 signaling in the anti-osteoclastogenic effects of RLE. RESULTS RLE alleviated bone erosion in joints of CIA rats. In both synovial tissues of CIA rats and IL-6/sIL-6R-stimulated RA-FLS, RLE downregulated the protein level of RANKL. In the co-culture system, RLE significantly and dose-dependently inhibited IL-6/sIL-6R-induced osteoclastogenesis. Mechanistic studies revealed that RLE lowered the protein level of phospho-STAT3 (Tyr705) in synovial tissues of CIA rats. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited the activation/phosphorylation of a STAT3 upstream kinase Janus kinase 2 (Tyr1007/1008) and STAT3 (Tyr705), decreased the nuclear localization of STAT3, lowered mRNA levels of STAT3-transcriptionally regulated genes IL-1β and TNF-α. RLE's inhibitory effects on RANKL production in RA-FLS gradually decreased when IL-6/sIL-6R doses increased. Over-activation of STAT3 diminished the inhibitory effects of RLE on RANKL production in IL-6/sIL-6R-stimulated RA-FLS, and attenuated the anti-osteoclastogenic effects of RLE in the co-culture system. CONCLUSION We, for the first time, demonstrated that suppressing STAT3 signaling contributes to the inhibition of RANKL production and osteoclastogenesis, and thereby supports the mechanisms responsible for the reduction in bone erosion in RLE-treated CIA rats. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug, and supports the notion that targeting STAT3 signaling is a viable strategy for managing bone erosion.
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Affiliation(s)
- Ying-Jie Chen
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jia-Ying Wu
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Wai-Chung Leung
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Yu-Xi Liu
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xiu-Qiong Fu
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jia-Qian Zhu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Ying Wu
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; JaneClare Transdermal TCM Therapy Laboratory, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Ji-Yao Chou
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Cheng-Le Yin
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Ya-Ping Wang
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xiao-Qi Wang
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jing-Xuan Bai
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Zheng-Zhi Wu
- Shenzhen Institute of Geriatrics, Shenzhen, China
| | - Zhi-Ling Yu
- Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China; Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; JaneClare Transdermal TCM Therapy Laboratory, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
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19
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Hu L, Chen Z, Li L, Jiang Z, Zhu L. Resveratrol decreases CD45 + CD206 - subtype macrophages in LPS-induced murine acute lung injury by SOCS3 signalling pathway. J Cell Mol Med 2019; 23:8101-8113. [PMID: 31559687 PMCID: PMC6850919 DOI: 10.1111/jcmm.14680] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 08/13/2019] [Accepted: 08/25/2019] [Indexed: 02/06/2023] Open
Abstract
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are life-threatening condition in critically ill patients. Resveratrol (Res), a natural polyphenol, has therapeutic effect in animal model with ALI; however, whether Res attenuates ALI through modulation of macrophage phenotypes in the animal model remains unknown. We in this study treated LPS-induced murine ALI with 30 mg/kg Res and observed significantly reduced severity of ALI in the Res-treated mice 48 hours after Res treatment. Neutrophil infiltrates were significantly reduced, accompanied with lower infiltration of CD45+ Siglec F- phenotype macrophages, but higher population of CD45+ Siglec F+ and CD45+ CD206+ alternatively activated macrophages (M2 cells) in the Res-treated mice with ALI. In addition, the expression of IL-1beta and CXCL15 cytokines was suppressed in the treated mice. However, Res treatment in mice with myeloid cell-restricted SOCS3 deficiency did not significantly attenuate ALI severity and failed to increase population of both CD45+ Siglec F+ and CD45+ CD206+ M2 subtype macrophages in the murine ALI. Further studies in wild-type macrophages revealed that Res treatment effectively reduced the expression of IL-6 and CXCL15, and increased the expression of arginase-1, SIRT1 and SOCS3. However, macrophages' lack of SOCS3 expression were resistant to the Res-induced suppression of IL-6 and CXCL15 in vitro. Thus, we conclude that Res suppressed CD45+ Siglec F- and CD45+ CD206- M1 subtype macrophages through SOCS3 signalling in the LPS-induced murine ALI.
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Affiliation(s)
- Lu Hu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhihong Chen
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liyang Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhilong Jiang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Zhu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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20
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Maruotti N, Corrado A, Rotondo C, Cantatore FP. Janus kinase inhibitors role in bone remodeling. J Cell Physiol 2019; 235:1915-1920. [DOI: 10.1002/jcp.29149] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/23/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Nicola Maruotti
- Department of Medical and Surgical Sciences Rheumatology Clinic University of Foggia Medical School Foggia Italy
| | - Addolorata Corrado
- Department of Medical and Surgical Sciences Rheumatology Clinic University of Foggia Medical School Foggia Italy
| | - Cinzia Rotondo
- Department of Medical and Surgical Sciences Rheumatology Clinic University of Foggia Medical School Foggia Italy
| | - Francesco Paolo Cantatore
- Department of Medical and Surgical Sciences Rheumatology Clinic University of Foggia Medical School Foggia Italy
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21
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Liu S, Yan R, Chen B, Pan Q, Chen Y, Hong J, Zhang L, Liu W, Wang S, Chen JL. Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6. Front Immunol 2019; 10:1843. [PMID: 31474976 PMCID: PMC6706793 DOI: 10.3389/fimmu.2019.01843] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 07/22/2019] [Indexed: 12/12/2022] Open
Abstract
Influenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mechanisms underlying such a response are poorly understood. Here we found from both in vivo and in vitro studies that IAV not only induced a surge of IL-6 release, but also greatly upregulated expression of suppressor of cytokine signaling-3 (SOCS3), the potent suppressor of IL-6-associated signal transducer and activator of transcription 3 (STAT3) signaling. Interestingly, there existed a cytokine-independent mechanism of the robust induction of SOCS3 by IAV at early stages of the infection. Furthermore, we employed SOCS3-knockdown transgenic mice (TG), and surprisingly observed from virus challenge experiments using these mice that disruption of SOCS3 expression provided significant protection against IAV infection, as evidenced by attenuated acute lung injury, a higher survival rate of infected animals and lower viral load in infected tissues as compared with those of wild-type littermates under the same condition. The activity of nuclear factor-kappa B (NFκB) and the expression of its target gene IL-6 were suppressed in SOCS3-knockdown A549 cells and the TG mice after infection with IAV. Moreover, we defined that enhanced STAT3 activity caused by SOCS3 silencing was important for the regulation of NFκB and IL-6. These findings establish a critical role for IL-6-STAT3-SOCS3 axis in the pathogenesis of IAV and suggest that influenza virus may have evolved a strategy to circumvent IL-6/STAT3-mediated immune response through upregulating SOCS3.
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Affiliation(s)
- Shasha Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Ruoxiang Yan
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Biao Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Qidong Pan
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yuhai Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Jinxuan Hong
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lianfeng Zhang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Beijing, China
| | - Wenjun Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Song Wang
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Ji-Long Chen
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
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22
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Chen Q, Lv J, Yang W, Xu B, Wang Z, Yu Z, Wu J, Yang Y, Han Y. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics 2019; 9:6424-6442. [PMID: 31588227 PMCID: PMC6771242 DOI: 10.7150/thno.35528] [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: 04/07/2019] [Accepted: 07/10/2019] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years. Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis. Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis. Therefore, the study of STAT3 inhibitors has gradually become a focal research topic. In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis. STAT3 in mitochondria is mentioned as well. Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis. Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis. Finally, we propose ideas that may help to solve these problems to some extent. Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.
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23
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Zhu J, Tang Y, Wu Q, Ji YC, Feng ZF, Kang FW. HIF-1α facilitates osteocyte-mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro. J Cell Physiol 2019; 234:21182-21192. [PMID: 31032948 DOI: 10.1002/jcp.28721] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/01/2019] [Accepted: 04/10/2019] [Indexed: 12/17/2022]
Abstract
Osteocytes, entrapped within the mineralized bone matrix, has been found to have numerous functions such as acting as an orchestrator of bone remodeling through regulation of both osteoclast and osteoblast activity and also functioning as an endocrine cell. Due to a specialized morphology and surrounding structure, osteocytes are more tolerant to hypoxia during osteoporosis, fracture, osteoarthritis, and orthodontic-orthognathic combination therapy. Hypoxia-inducible factor-1α (HIF-1α) is one of the master regulators of hypoxia reactions, playing an important role in bone modeling, remodeling, and homeostasis. This study aimed to investigate the pivotal functional role of HIF-1α in osteocytes initiating of bone remodeling under hypoxia. In the present study, the osteoclasts formation induced by RAW264.7 was significantly promoted in conditioned media (CM) from osteocytic MLO-Y4 exposed to hypoxia in vitro. Therefore, hypoxic MLO-Y4 cells simulated by 100 μmol/L CoCl2 or 2% O2 stably expressed HIF-1α proteins and upregulated the expression of receptor activator of nuclear factor-κB ligand (RANKL) at both the messenger RNA (mRNA) and protein level. Furthermore, with the Knockdown of HIF-1α, the expression of RANKL mRNA and protein decreased after transient transfection. In addition, the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) was also correlated with HIF-1α and RANKL levels under hypoxia. Then AG490, a JAK2 inhibitor, inhibited p-JAK2, p-STAT3 and RANKL expression. It was possible that AG490 disturbed the contact of HIF-1α and RANKL by JAK2/STAT3 pathway, influencing osteoclastogenesis. Our findings suggested that HIF-1α promoted the expression of RANKL by activating JAK2/STAT3 pathway in MLO-Y4 cells, and enhanced osteocyte-mediated osteoclastic differentiation in vitro.
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Affiliation(s)
- Jie Zhu
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yi Tang
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Qing Wu
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Ying-Chen Ji
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Zi-Fan Feng
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Fei-Wu Kang
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Tongji University, Shanghai, China.,Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
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Niu HQ, Zhao WP, Zhao XC, Luo J, Qin KL, Chen KL, Li XF. Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2/STAT3 and p38MAPK signaling pathway. Int Immunopharmacol 2018; 61:45-53. [DOI: 10.1016/j.intimp.2018.05.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 05/16/2018] [Accepted: 05/19/2018] [Indexed: 01/01/2023]
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25
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Wang Z, Tan J, Lei L, Sun W, Wu Y, Ding P, Chen L. The positive effects of secreting cytokines IL-17 and IFN-γ on the early-stage differentiation and negative effects on the calcification of primary osteoblasts in vitro. Int Immunopharmacol 2018; 57:1-10. [PMID: 29438885 DOI: 10.1016/j.intimp.2018.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 02/03/2018] [Accepted: 02/06/2018] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Interleukin-17 (IL-17) and interferon-gamma (IFN-γ) are all pro-inflammatory cytokines produced by specific subsets of T-cells and are also considered crucial regulators in bone remodeling, but their effects on osteogenesis have not been carefully studied. So, this study aimed to investigate the effects of secreting cytokines IL-17 and IFN-γ on the osteogenesis of primary osteoblasts and to clarify the potential roles of the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway in bone remodeling. METHODS The proliferation of osteoblasts was evaluated by MTT assay. Osteogenic activity was tested by alkaline phosphatase (ALP) activity assay and alizarin red staining. The mRNA levels of ALP, osteocalcin, osteoprotegerin (OPG), Runt-related transcription factor 2 (Runx2) and receptor activator of nuclear factor-kappa B ligand (RANKL) were also measured by real-time quantitative PCR. The JAK2-STAT3 pathway was evaluated by Western blot. RESULTS Osteoblasts showed no obvious proliferation when treated with IL-17 and/or IFN-γ, but higher ALP activities were observed in primary osteoblasts treated with IL-17 or IL-17 + IFN-γ in induction medium. We also found that IL-17 could promote the gene expression of Alp, Runx2, Osteocalcin, Opg, and Rankl, while IFN-γ might attenuate this effect. Nevertheless, IL-17 and IFN-γ exhibited an inhibitory effect on the calcification of primary osteoblasts. We also found that IL-17 could directly facilitate RANKL expressions by JAK2-STAT3 pathway. CONCLUSION The positive effects of IL-17 and IFN-γ on the early-stage differentiation and the negative effects on the calcification of murine calvarial osteoblasts contribute to our understanding of the role and interaction of inflammatory factors in the bone remodeling and as fundamental mechanisms involved in the destruction of alveolar bone.
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Affiliation(s)
- Zhongxiu Wang
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingyi Tan
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lihong Lei
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilian Sun
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanmin Wu
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Peihui Ding
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lili Chen
- Department of Oral Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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26
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Miao P, Zhou XW, Wang P, Zhao R, Chen N, Hu CY, Chen XH, Qian L, Yu QW, Zhang JY, Xu R, He DY, Xiao LB, Li P, Lu M, Zhang DQ. Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS. Oncotarget 2018; 9:20366-20376. [PMID: 29755657 PMCID: PMC5945543 DOI: 10.18632/oncotarget.23917] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022] Open
Abstract
We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody–induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase–STAT3 pathway downregulation. The IL-6–soluble IL-6Rα–gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.
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Affiliation(s)
- Ping Miao
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Wei Zhou
- Reproductive Medical Center of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Wang
- Shanghai Jiao Tong University School of Medicine, XinHua Hospital, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ninan Chen
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Ying Hu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Central laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
| | - Xue Hua Chen
- Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liu Qian
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Wen Yu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji Ying Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Xu
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Dong Yi He
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Lian Bo Xiao
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Pu Li
- Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Dong Qing Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Liu J, Fei D, Xing J, Du J. Retracted: MicroRNA-29a inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes by repressing STAT3. Biomed Pharmacother 2017; 96:173-181. [PMID: 28987940 DOI: 10.1016/j.biopha.2017.09.120] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/16/2017] [Accepted: 09/23/2017] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) with aberrant expression of microRNA (miRNA) have been reported to be involved in the initiation, progression, and perpetuation of rheumatoid arthritis (RA). In this study, we explored the biological function and underlying mechanism of microRNA-29a (miR-29a) in cultured RA-FLS from RA patients. The expression of miR-29a in serum, synovial tissues, and FLS from RA patients and health donors was detected by real-time quantitative RT-PCR (qRT-PCR). The effects of miR-29a on cell proliferation, apoptosis, and inflammatory cytokine levels in RA-FLS were also determined using Counting Assay Kit-8 (CCK-8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA) respectively. Luciferase reporter assay was carried out to identify the target genes of miR-29a. We observed that expression of miR-29a was markedly downregulated in serum, synovial tissues and FLS of RA patients. miR-29a overexpression in RA-FLS significantly inhibited proliferation, promoted apoptosis, and suppressed expression of inflammatory cytokines. Signal transducer and activator of transcription 3 (STAT3) was identified to be a direct target of miR-29a in RA-FLS. miR-29a overexpression suppressed the expression of STAT3, as well as phosphorylated STAT3(p-STAT3) and its downstream targets protein (Cyclin D1 and Bcl-2). In addition, the levels of miR-29a were inversely correlated with that of STAT3 in synovial tissues. Rescue experiments showed that overexpression of STAT3 effectively reversed the effect of miR-29a on proliferation and apoptosis in RA-FLS. These data indicate that miR-29a inhibits proliferation and induces apoptosis in RA-FLS by targeting STAT3, suggesting that promoting miR-29a expression may yield therapeutic benefits in the treatment of RA.
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Affiliation(s)
- Jinxiang Liu
- Department of Pediatric Rheumatology and Allergy, the First Affiliated Bethune Hospital, Jilin University, Changchun 130021, PR China
| | - Dan Fei
- Ultrasonographic Department, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China
| | - Jie Xing
- Ultrasonographic Department, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China
| | - Juan Du
- Department of Rheumatology and Immunology, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China.
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The immunoglobulin D Fc receptor expressed on fibroblast-like synoviocytes from patients with rheumatoid arthritis contributes to the cell activation. Acta Pharmacol Sin 2017; 38:1466-1474. [PMID: 28770826 DOI: 10.1038/aps.2017.105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 04/04/2017] [Indexed: 12/27/2022]
Abstract
Immunoglobulin IgD might play an important role in autoimmune diseases, but the function of IgD has remained elusive, despite multiple attempts to define its biological function. Fibroblast-like synoviocytes (FLSs) are specialized cells of the synovium that play a key role in the pathogenesis of rheumatoid arthritis (RA). In this study we explored the possible roles of excessive IgD expression on the function of FLSs from RA patients (RA-FLSs). We showed that IgD Fc receptor (IgDR) was constitutively expressed on FLSs, and was significantly elevated in RA-FLSs compared with FLSs prepared from synovial tissues of healthy controls (HC-FLSs). Furthermore, IgDR was mainly detected on the cell surface and in the cytoplasm. We further detected the intrinsic binding affinity of IgD to IgDR on HC-FLSs with an equilibrium dissociation constant (KD) of 0.067 nmol/L. Incubation of RA-FLSs with IgD (1-10 μg/mL) for 48 h dose-dependently promoted the expression of IgDR, and stimulated the production of inflammatory cytokines and chemokines, such as IL-1β, IL-6, monocyte chemotactic protein (MCP)-1, TNF-α and receptor activator of nuclear factor-κB ligand (RANKL), thus potentially contributing to IgD-IgDR crosslinking. Moreover, incubation with IgD (0.1-10 μg/mL) for 48 h dose-dependently enhanced viability for both HC-FLSs and RA-FLSs. Our results demonstrate that IgDR is expressed on RA-FLSs and contributes to the activation of FLSs, and suggest that IgD-IgDR is a potential novel immunotherapeutic target for the management of RA.
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Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis. Int J Mol Sci 2017; 18:ijms18030484. [PMID: 28245561 PMCID: PMC5372500 DOI: 10.3390/ijms18030484] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 01/31/2017] [Accepted: 02/16/2017] [Indexed: 12/28/2022] Open
Abstract
Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-Activated/Mitogen-Activated Protein Kinase (SAPK/MAPK) and phosphatidylinositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathways which regulate numerous cellular responses. However, cytokine gene expression, matrix metalloproteinase gene expression and aberrant immune cell and synoviocyte survival via reduced apoptosis are most critical in the context of inflammation characteristic of RA and OA. Negative regulation of JAK/STAT signaling is controlled by Suppressor of Cytokine Signaling (SOCS) proteins. SOCS is produced at lower levels in RA and OA. In addition, gaining further insight into the role played in RA and OA pathology by the inhibitors of the apoptosis protein family, cellular inhibitor of apoptosis protein-1, -2 (c-IAP1, c-IAP2), X (cross)-linked inhibitor of apoptosis protein (XIAP), protein inhibitor of activated STAT (PIAS), and survivin (human) as well as SOCS appears to be a worthy endeavor going forward.
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30
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Hirai T, Ikeda K, Fujishiro M, Tsushima H, Hayakawa K, Suzuki S, Yamaguchi A, Nozawa K, Morimoto S, Takasaki Y, Ogawa H, Takamori K, Tamura N, Sekigawa I. The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study. Clin Rheumatol 2016; 36:51-58. [PMID: 27783236 DOI: 10.1007/s10067-016-3458-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 10/16/2016] [Indexed: 02/03/2023]
Abstract
The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.
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Affiliation(s)
- Takuya Hirai
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
- Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan
| | - Keigo Ikeda
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
- Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.
| | - Maki Fujishiro
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Hiroshi Tsushima
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Kunihiro Hayakawa
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Satoshi Suzuki
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Ayako Yamaguchi
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental health, Kitakyushu, Fukuoka, Japan
| | - Kazuhisa Nozawa
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shinji Morimoto
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
- Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan
| | - Yoshinari Takasaki
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hideoki Ogawa
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Kenji Takamori
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Iwao Sekigawa
- Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
- Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan
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31
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Christensen AD, Haase C, Cook AD, Hamilton JA. K/BxN Serum-Transfer Arthritis as a Model for Human Inflammatory Arthritis. Front Immunol 2016; 7:213. [PMID: 27313578 PMCID: PMC4889615 DOI: 10.3389/fimmu.2016.00213] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 05/17/2016] [Indexed: 12/29/2022] Open
Abstract
The K/BxN serum-transfer arthritis (STA) model is a murine model in which the immunological mechanisms occurring in rheumatoid arthritis (RA) and other arthritides can be studied. To induce K/BxN STA, serum from arthritic transgenic K/BxN mice is transferred to naive mice and manifestations of arthritis occur a few days later. The inflammatory response in the model is driven by autoantibodies against the ubiquitously expressed self-antigen, glucose-6-phosphate isomerase (G6PI), leading to the formation of immune complexes that drive the activation of different innate immune cells such as neutrophils, macrophages, and possibly mast cells. The pathogenesis further involves a range of immune mediators including cytokines, chemokines, complement factors, Toll-like receptors, Fc receptors, and integrins, as well as factors involved in pain and bone erosion. Hence, even though the K/BxN STA model mimics only the effector phase of RA, it still involves a wide range of relevant disease mediators. Additionally, as a murine model for arthritis, the K/BxN STA model has some obvious advantages. First, it has a rapid and robust onset of arthritis with 100% incidence in genetically identical animals. Second, it can be induced in a wide range of strain backgrounds and can therefore also be induced in gene-deficient strains to study the specific importance of disease mediators. Even though G6PI might not be an essential autoantigen, for example, in RA, the K/BxN STA model is a useful tool to understand how autoantibodies, in general, drive the progression of arthritis by interacting with downstream components of the innate immune system. Finally, the model has also proven useful as a model wherein arthritic pain can be studied. Taken together, these features make the K/BxN STA model a relevant one for RA, and it is a potentially valuable tool, especially for the preclinical screening of new therapeutic targets for RA and perhaps other forms of inflammatory arthritis. Here, we describe the molecular and cellular pathways in the development of K/BxN STA focusing on the recent advances in the understanding of the important mechanisms. Additionally, this review provides a comparison of the K/BxN STA model to some other arthritis models.
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Affiliation(s)
- Anne D Christensen
- Department of Medicine, University of Melbourne, Parkville, VIC, Australia; Novo Nordisk A/S, Måløv, Denmark
| | | | - Andrew D Cook
- Department of Medicine, University of Melbourne , Parkville, VIC , Australia
| | - John A Hamilton
- Department of Medicine, University of Melbourne , Parkville, VIC , Australia
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Kaneshiro S, Ebina K, Hirao M, Tsuboi H, Nishikawa M, Nampei A, Nagayama Y, Takahi K, Noguchi T, Owaki H, Hashimoto J, Yoshikawa H. The efficacy and safety of additional administration of tacrolimus in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab. Mod Rheumatol 2016; 27:42-49. [DOI: 10.1080/14397595.2016.1181315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Shoichi Kaneshiro
- Department of Orthopaedic Surgery, Japan Community Healthcare Organization, Osaka Hospital, Osaka, Japan,
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan,
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, Osaka, Japan,
| | - Kosuke Ebina
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan,
| | - Makoto Hirao
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan,
| | - Hideki Tsuboi
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, Osaka, Japan,
| | - Masataka Nishikawa
- Department of Orthopaedic Surgery, Japan Community Healthcare Organization, Osaka Hospital, Osaka, Japan,
| | - Akihide Nampei
- Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan,
| | - Yoshio Nagayama
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, Osaka, Japan,
| | - Koichiro Takahi
- Department of Orthopaedic Surgery, Toneyama National Hospital, Osaka, Japan, and
| | - Takaaki Noguchi
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan,
| | - Hajime Owaki
- Department of Orthopaedic Surgery, Japan Community Healthcare Organization, Osaka Hospital, Osaka, Japan,
| | - Jun Hashimoto
- Department of Rheumatology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Hideki Yoshikawa
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan,
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33
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Lou L, Liu Y, Zhou J, Wei Y, Deng J, Dong B, Chai L. Chlorogenic acid and luteolin synergistically inhibit the proliferation of interleukin-1β-induced fibroblast-like synoviocytes through regulating the activation of NF-κB and JAK/STAT-signaling pathways. Immunopharmacol Immunotoxicol 2015; 37:499-507. [DOI: 10.3109/08923973.2015.1095763] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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34
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Baillet A, Gossec L, Paternotte S, Etcheto A, Combe B, Meyer O, Mariette X, Gottenberg JE, Dougados M. Evaluation of Serum Interleukin-6 Level as a Surrogate Marker of Synovial Inflammation and as a Factor of Structural Progression in Early Rheumatoid Arthritis: Results From a French National Multicenter Cohort. Arthritis Care Res (Hoboken) 2015; 67:905-12. [DOI: 10.1002/acr.22513] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 10/05/2014] [Accepted: 11/04/2014] [Indexed: 01/09/2023]
Affiliation(s)
| | - Laure Gossec
- UPMC Université Paris 06, GRC-UPMC 08 (EEMOIS), Assistance Publique Hôpitaux de Paris, Pitié Salpêtrière Hospital; Paris France
| | - Simon Paternotte
- Paris-Descartes University, Assistance Publique Hôpitaux de Paris, Cochin Hospital; Paris France
| | - Adrien Etcheto
- Paris-Descartes University, Assistance Publique Hôpitaux de Paris, Cochin Hospital; Paris France
| | - Bernard Combe
- Lapeyronie University Hospital, Montpellier I University; Montpellier France
| | - Olivier Meyer
- Université Paris 7 Denis Diderot, UFR de Médecine, and Assistance Publique Hôpitaux de Paris, Hôpital Bichat; Paris France
| | - Xavier Mariette
- Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Université Paris-Sud, Institut Pour la Santé et la Recherche Médicale Paris, France
| | | | - Maxime Dougados
- Paris-Descartes University, Assistance Publique Hôpitaux de Paris, Cochin Hospital; Paris France
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35
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Rozman Peterka T, Grahek R, Hren J, Bastarda A, Bergles J, Urleb U. Solid state compatibility study and characterization of a novel degradation product of tacrolimus in formulation. J Pharm Biomed Anal 2015; 110:67-75. [PMID: 25804434 DOI: 10.1016/j.jpba.2015.02.047] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 02/21/2015] [Accepted: 02/23/2015] [Indexed: 11/16/2022]
Abstract
Tacrolimus is macrolide drug that is widely used as a potent immunosuppressant. In the present work compatibility testing was conducted on physical mixtures of tacrolimus with excipients and on compatibility mixtures prepared by the simulation of manufacturing process used for the final drug product preparation. Increase in one major degradation product was detected in the presence of magnesium stearate based upon UHPLC analysis. The degradation product was isolated by preparative HPLC and its structure was elucidated by NMR and MS studies. Mechanism of the formation of this degradation product is proposed based on complementary degradation studies in a solution and structural elucidation data. The structure was proven to be alpha-hydroxy acid which is formed from the parent tacrolimus molecule through a benzilic acid type rearrangement reaction in the presence of divalent metallic cations. Degradation is facilitated at higher pH values.
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Affiliation(s)
| | - Rok Grahek
- Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
| | - Jure Hren
- Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
| | - Andrej Bastarda
- Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
| | - Jure Bergles
- Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
| | - Uroš Urleb
- Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
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36
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Sundaram K, Sambandam Y, Balasubramanian S, Pillai B, Voelkel-Johnson C, Ries WL, Reddy SV. STAT-6 mediates TRAIL induced RANK ligand expression in stromal/preosteoblast cells. Bone 2015; 71:137-44. [PMID: 25445452 DOI: 10.1016/j.bone.2014.10.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 10/14/2014] [Accepted: 10/23/2014] [Indexed: 02/02/2023]
Abstract
Receptor activator of nuclear factor kappa-B ligand (RANKL) is a critical osteoclastogenic factor expressed in bone marrow stromal/osteoblast lineage cells. Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) levels are elevated in pathologic conditions such as multiple myeloma and inflammatory arthritis, and have been positively correlated with osteolytic markers. Osteoprotegerin (OPG) which inhibits osteoclastogenesis is a decoy receptor for RANKL and also known to interact with TRAIL. Herein, we show that TRAIL increases DR5 and DcR1 receptors but no change in the levels of DR4 and DcR2 expression in human bone marrow derived stromal/preosteoblast (SAKA-T) cell line. We further demonstrated that TRAIL treatment significantly decreased OPG mRNA expression. Interestingly, TRAIL treatment induced RANKL mRNA expression in these cells. In addition, TRAIL significantly increased NF-kB and c-Jun N-terminal kinase (JNK) activity. Human transcription factor array screening by real-time RT-PCR identified TRAIL up-regulation of the signal transducers and activators of the transcription (STAT)-6 expression in SAKA-T cells. TRAIL stimulation induced p-STAT-6 expression in human bone marrow derived primary stromal/preosteoblast cells. Confocal microscopy analysis further revealed p-STAT-6 nuclear localization in SAKA-T cells. Chromatin immunoprecipitation (ChIP) assay confirmed p-STAT-6 binding to the hRANKL gene distal promoter region. In addition, siRNA suppression of STAT-6 expression inhibits TRAIL increased hRANKL gene promoter activity. Thus, our results suggest that TRAIL induces RANKL expression through a STAT-6 dependent transcriptional regulatory mechanism in bone marrow stromal/preosteoblast cells.
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Affiliation(s)
- Kumaran Sundaram
- Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA
| | - Yuvaraj Sambandam
- Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA
| | | | - Balakrishnan Pillai
- Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA
| | | | - William L Ries
- College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Sakamuri V Reddy
- Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA.
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37
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Hosokawa Y, Shindo S, Hosokawa I, Ozaki K, Matsuo T. IL-6 trans-signaling enhances CCL20 production from IL-1β-stimulated human periodontal ligament cells. Inflammation 2014; 37:381-6. [PMID: 24081898 DOI: 10.1007/s10753-013-9750-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
CC chemokine ligand 20 (CCL20) plays a central role in the recruitment of CCR6-expressing cells, including Th17 cells which are related to bone resorption in periodontal lesions and thus in the development of periodontal disease. IL-6 is an important cytokine that is associated with the pathogenesis of periodontitis. However, the effect of IL-6 on CCL20 production is uncertain. The aim of this study was to examine whether IL-6 could modify CCL20 expression in human periodontal ligament cells (HPDLCs). HPDLCs expressed gp130 but did not express IL-6R on the surface of HPDLCs. So, IL-6 trans-signaling is important to recognize IL-6 by HPDLCs. IL-6/sIL-6R stimulation enhanced CCL20 production in IL-1β-stimulated HPDLCs. IL-6 produced from IL-1β-stimulated HPDLCs with sIL-6R could increase CCL20 production in HPDLCs with sIL-6R. Signal transducer and activator of transcription (STAT)3 activation was related to CCL20 production in IL-1β and IL-6/sIL-6R-stimulated HPDLCs. Our data suggests that HPDLCs, in response to IL-6, sIL-6R, and IL-1β, may shift chemokine production to that favoring CCR6-expressing cells recruitment in periodontal lesions.
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Affiliation(s)
- Yoshitaka Hosokawa
- Department of Conservative Dentistry and Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8504, Japan,
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Hashizume M, Tan SL, Takano J, Ohsawa K, Hasada I, Hanasaki A, Ito I, Mihara M, Nishida K. Tocilizumab, a humanized anti-IL-6R antibody, as an emerging therapeutic option for rheumatoid arthritis: molecular and cellular mechanistic insights. Int Rev Immunol 2014; 34:265-79. [PMID: 25099958 DOI: 10.3109/08830185.2014.938325] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds and neutralizes IL-6R, resulting in the inhibition of various IL-6-mediated biological activities, including inflammation-related, immunomodulatory and tissue/matrix remodelling effects. Randomized, double-blind, controlled phase III studies and a number of early clinical observational studies have shown that treatment with TCZ results in rapid and sustained improvement in the signs and symptoms of RA among different patient populations. These studies have established the efficacy and safety of TCZ. Here, we review the pleiotropic functions of IL-6 and how it impinges on many aspects of RA pathogenesis, and highlight the clinical experience to date with TCZ as an emerging new treatment option for RA.
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Affiliation(s)
- Misato Hashizume
- Chugai Pharmaceutical Co., Ltd. , Fuji-Gotemba Research Laboratories, Gotemba , Japan
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Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, Sakai T, Nakamura M, Motokawa S, Nakamura T, Kawakami A. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol 2014; 175:208-14. [PMID: 24665995 DOI: 10.1111/cei.12234] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2013] [Indexed: 12/18/2022] Open
Abstract
The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 μg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 μg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib.
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Affiliation(s)
- K Migita
- Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Omura, Japan
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P-glycoprotein and drug resistance in systemic autoimmune diseases. Int J Mol Sci 2014; 15:4965-76. [PMID: 24658440 PMCID: PMC3975434 DOI: 10.3390/ijms15034965] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 03/06/2014] [Accepted: 03/13/2014] [Indexed: 02/07/2023] Open
Abstract
Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.
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Saravanan S, Islam VIH, Babu NP, Pandikumar P, Thirugnanasambantham K, Chellappandian M, Raj CSD, Paulraj MG, Ignacimuthu S. Swertiamarin attenuates inflammation mediators via modulating NF-κB/I κB and JAK2/STAT3 transcription factors in adjuvant induced arthritis. Eur J Pharm Sci 2014; 56:70-86. [PMID: 24582615 DOI: 10.1016/j.ejps.2014.02.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 01/26/2014] [Accepted: 02/11/2014] [Indexed: 12/23/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that leads to pannus formation followed by severe joint destruction, characterized by synovial hyperplasia, inflammation and angiogenesis. Swertiamarin is a secoiridoid glycoside that is used as an anti-inflammatory compound, mainly found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used in Indian system of traditional medicine. In the present study, the effect of swertiamarin was evlauated in experimental adjuvant arthritis animal model by the estimation of biochemical (paw thickness, lysosomal enzymes, and urinary degradative products) parameters, proinflammatory cytokines and enzymes along with histopathological and radiographic observations. The proteins of phosphorylated NF-κB/IκB and JAK2/STAT3 transcription factors were also quantified from experimental animals as well as LPS induced RAW 264.7 macrophage cells. In in silico analysis, swertiamarin was docked with proinflammatory enzymes to confirm its potential. The administration of swertiamarin (2, 5, 10mg/kg bw) significantly (P⩽0.05) inhibited the levels of paw thickness, lysosomal enzymes and increased the body weight of experimental animals in a dose dependent manner. In molecular analysis, the treatment decreased the release of proinflammatory cytokines (IL1, TNF, IL-6) and proangiogenic enzymes (MMPs, iNOS, PGE2, PPARγ and COX-2); and also significantly (P⩽0.05) increased the levels of antiinflammatory proteins (IL-10, IL-4) when compared to the disease groups. The swertiamarin treatment significantly (P⩽0.05) inhibited the release of NF-κB p65, p-IκBα, p-JAK2 and p-STAT3 signaling proteins levels on both experimental animals and LPS induced cells. Histopathological and radiological analysis evidenced the curative effect of swertiamarin on bone destruction. The docking studies of swertiamarin on proinflammatory enzymes supported the results from the in vivo experiments. Thus the swertiamarin inhibited the development of arthritis by modulating NF-κB/IκB and JAK2/STAT3 signaling. These findings suggested that swertiamarin acted as an anti-rheumatic agent.
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Affiliation(s)
- S Saravanan
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India
| | - V I Hairul Islam
- Division of Microbiology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Pondicherry Centre for Biological Sciences, Pondicherry 605 005, Pondicherry, India
| | - N Prakash Babu
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India
| | - P Pandikumar
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India
| | | | - M Chellappandian
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India
| | - C Simon Durai Raj
- Department of Pathology, Sri Ramachandra Medical College and Research Institute, Porur, Chennai 600 116, Tamil Nadu, India
| | - M Gabriel Paulraj
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India
| | - S Ignacimuthu
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Division of Microbiology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Department of Botany and Microbiology, College of Science, King Saud University, P.O.Box 2455, Riyadh, 1145, Saudi Arabia.
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Gao A, Van Dyke TE. Role of suppressors of cytokine signaling 3 in bone inflammatory responses. Front Immunol 2014; 4:506. [PMID: 24454312 PMCID: PMC3887271 DOI: 10.3389/fimmu.2013.00506] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 12/21/2013] [Indexed: 12/23/2022] Open
Abstract
Suppressor of cytokine signaling 3 (SOCS3) is a potent regulator of cytokine signaling in macrophages and T cells. In recent studies, evidence has been provided for SOCS3 activation in all major bone cells including osteoclasts, chondrocytes, synoviocytes, and osteoblasts. The investigation of SOCS3 function in bone remodeling systems implicates SOCS3 as a key signaling molecule in bone cell-mediated inflammatory responses. Both pro- and anti-inflammatory functions of SOCS3 have been demonstrated in different types of bone cells. This review provides an overview of the important role of SOCS3 in inflammatory responses of various bone cells and in bone inflammatory disorders such as periodontal disease and arthritis. Understanding the roles of SOCS3 in inflammatory diseases of bone and joints such as arthritis, osteomyelitis, and periodontal diseases is critical to revealing insights into signaling pathways that can be manipulated in potential therapeutic approaches.
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Affiliation(s)
- Anqi Gao
- Department of Applied Oral Sciences, The Forsyth Institute , Cambridge, MA , USA
| | - Thomas E Van Dyke
- Department of Applied Oral Sciences, The Forsyth Institute , Cambridge, MA , USA
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