Journal
ARTHRITIS AND RHEUMATISM
Volume 56, Issue 7, Pages 2244-2254Publisher
WILEY
DOI: 10.1002/art.22732
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Funding
- Wellcome Trust Funding Source: Medline
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Objective. Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon-gamma (IFN gamma) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin-1 beta [IL-1 beta] and tumor necrosis factor alpha [TNF alpha]) in modulating inflammation and arthritis in vitro and in vivo. Methods. Monarticular antigen-induced arthritis (AIA) was initiated in IFN gamma-deficient (IFN gamma(-/-)) mice and age-matched wild-type (IFN-gamma(+/+)) mice. joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFN gamma in regulating IL-1 beta- and TNF alpha-driven CXCL8 and CCL2 production was quantified by enzyme-linked immunosorbent assay. Results. In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFN gamma. IFN gamma appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast-like synoviocytes, IFN gamma modulated both IL-1 beta- and TNF alpha-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production. Conclusion. IFN gamma exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFN gamma signaling in the treatment of inflammatory arthritides.
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