Interferon-gamma protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints.
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 (IFNgamma) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin-1beta [IL-1beta] and tumor necrosis factor alpha [TNFalpha]) in modulating inflammation and arthritis in vitro and in vivo.


METHODS
Monarticular antigen-induced arthritis (AIA) was initiated in IFNgamma-deficient (IFNgamma(-/-)) mice and age-matched wild-type (IFNgamma(+/+)) 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 IFNgamma in regulating IL-1beta- and TNFalpha-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 IFNgamma. IFNgamma appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast-like synoviocytes, IFNgamma modulated both IL-1beta- and TNFalpha-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production.


CONCLUSIONS
IFNgamma 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 IFNgamma signaling in the treatment of inflammatory arthritides.
Williams
Anwen S
AS
Wales College of Medicine, Cardiff University, Heath Park, Cardiff, UK. wmdasw@cardiff.ac.uk
Richards
Peter J
PJ
Thomas
Eleri
E
Carty
Sara
S
Nowell
Mari A
MA
Goodfellow
Rhian M
RM
Dent
Colin M
CM
Williams
Bryan D
BD
Jones
Simon A
SA
Topley
Nicholas
N
D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D018450:Disease Progression; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000172:deficiency* / Q000502:physiology*; D007596:Joints / Q000098:blood supply* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*
D007371:Interferon-gamma