期刊
INTERNATIONAL IMMUNOLOGY
卷 23, 期 11, 页码 701-712出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxr077
关键词
chronic inflammation; collagen-induced arthritis; IL-6; joint destruction; rheumatoid arthritis
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- National Institute of Biomedical Innovation
- Mochida Memorial Foundation
- Uehara Memorial Foundation
- Precursory Research for Embryonic Science and Technology
- Keio Kanrinmaru project, Japan
- Keio University
- Grants-in-Aid for Scientific Research [21689040, 23590573] Funding Source: KAKEN
Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1 beta, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1 beta were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.
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