IL-1 is a proinflammatory cytokine that plays a major role in arthritis. IL-1 receptor antagonist (IL-1Ra) is a natural inhibitor of IL-1. IL-1Ra refers to four isoforms, one secreted (sIL-1RA) and three intracellular (icIL-1RA1, 2, 3) peptides. The purpose of this study was to examine the regulation of production of IL-1Ra isoforms in collagen-induced arthritis (CIA), an experimental model for rheumatoid arthritis.

Results: IL-1band sIL-1Ra mRNA were present at low levels in the normal synovium, and expression of both was enhanced in arthritic joints. In contrast, icIL-1Ra1 mRNA was detected only in arthritic joints and was the predominant intracellular isoform found in inflamed synovium. In situ hybridization determined that icIL-1Ra1 was produced by macrophages and fibroblast within the inflamed synovium tissue. By Western blot analysis, icIL-1Ra1 levels were observed to increase and peak by day 20 after the appearance of the arthritis, and remain detectable for up to 60 days. IL-1bmRNA levels, in contrast, increased early in the development of CIA but declined thereafter. Consequently, the ratio of IL-1b:IL-1Ra was > 1 early in CIA but dropped to levels < 1 at later time points. The ratio appeared to correlate with disease severity in the affected joints.

Editorial Comment: The combination of decreased production of ILi1band elevated levels of icIL-1Ra1 during the course of CIA was associated with a change in the IL-1b:IL-1Ra balance. These results suggest that icIL-1Ra1 plays a role in the resolution of murine CIA. Prior to this, only the soluble form of IL-1Ra was thought to play an antiinflammatory role in arthritis. These data, although circumstantial, provide support for an antiinflammatory role for intracellular forms of IL-1Ra.

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