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IL-1 and TNF -initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis
Abstract
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-1β, 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-1β 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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“These cytokines in turn stimulate the expression of RANKL in osteoblasts,73 enhancing the osteoclastogenesis previously activated by the release of ATP by apoptotic osteocytes.66”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [73]
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Metadata
- Authors
- Mori, T., Miyamoto, T., Yoshida, H., Asakawa, M., Kawasumi, M., Kobayashi, T., Morioka, H., Chiba, K., Toyama, Y., & Yoshimura, A.
- Affiliations
- Keio University (JP)
- Venue
- International Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-21
- Volume
- 23
- Issue
- 11
- Pages
- 701-712
- ISSN
- 0953-8178 (ISSN-L)
- 1460-2377
- OpenAlex
- W2127938598
- Cited by
- 328
- References
- 49
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 16 · 2023: 25 · 2022: 27 · 2021: 33 · 2020: 33 · 2019: 33 · 2018: 28 · 2017: 22 · 2016: 13 · 2015: 15 · 2014: 10 · 2013: 15 · 2012: 9
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21689040, 23590573)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- rheumatoid arthritis, STAT3 signaling, IL-1β, TNF-α, interleukin-6, IL-6 family cytokines, RANKL, osteoclastogenesis, joint destruction, collagen-induced arthritis, leukemia inhibitory factor, osteoblasts, fibroblasts, chronic inflammation
- MeSH terms
- Animals, Arthritis, Experimental, Arthritis, Rheumatoid, Chronic Disease, Enzyme Inhibitors, Fibroblasts, Humans, Inflammation, Joints, Mice, Inbred C57BL, Mice, Inbred DBA, Osteoclasts, Piperidines, Pyrimidines, Pyrroles, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Gene Expression, STAT3 Transcription Factor, Mice, RANK Ligand, Interleukin-1beta
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