Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Abstract

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-γ (IFNγ) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin-1β [IL-1β] and tumor necrosis factor α [TNFα]) in modulating inflammation and arthritis in vitro and in vivo. Methods Monarticular antigen-induced arthritis (AIA) was initiated in IFNγ-deficient (IFNγ^−/−) mice and age-matched wild-type (IFNγ^+/+) 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 IFNγ in regulating IL-1β– and TNFα-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 IFNγ. IFNγ appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast-like synoviocytes, IFNγ modulated both IL-1β– and TNFα-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production. Conclusion IFNγ 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 IFNγ signaling in the treatment of inflammatory arthritides.