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Effect of IL-18 on synovial cell subsets and its regulation by IL-18BP

IL-18 has multiple biological activities that are important in generating Th1 responses and inflammatory tissue damage. IL-18 has molecular similarity with IL-1, and IL-18 receptor (IL-18R) belongs to the superfamily of IL-1 receptor. In our previous studies, IL-18 was detected in both synovial fluid and serum samples from patients with rheumatoid arthritis (RA) and serum IL-18 levels correlated with disease activity as assessed by levels of serum CRP and erythrocyte sedimentation rate. We then examined the synovial expression of IL-18 in RA. Isolated RA tissue cells could spontaneously produce high amounts of IL-18 in culture. In RA synovium, IL-18-positive cells were frequently located in both the lining and sublining layer, but not in lymphocyte aggregates. Both CD14+ macrophages and synoviocytes isolated from RA synovium expressed detectable levels of IL-18 mRNA. Using IL-1 as a positive control, we next examined the effect of IL-18 on IL-6 production in RA synoviocyte culture. In contrast to IL-1, IL-18 has no effect on IL-6 production from RA synoviocyte at both mRNA and protein levels. This lack of response appears to be related to defective receptor expression. Isolated RA tissue cells as well as nonstimulated RA synoviocytes expressed detectable levels of mRNA of IL-18R alpha chain, but IL-18R beta chain, which is critical for IL-18 signal transduction, was detected in RA tissue cells but not in purified synoviocytes, even if these cells were stimulated with IL-1β, TNF-α, or supernatant of RA synovium culture. RA synovial cells responded to IL-18. IFN-γ production by IL-12-stimulated RA synovial tissue cells was synergistically enhanced by IL-18, and it was partially inhibited by addition of IL-18 binding protein (IL-18BP). Upregulation of IL-18R beta mRNA levels in RA synovial tissue cells with IL-12 stimulation could explain this synergy. These results indicate a complex effect of IL-18 on various cell subsets found in RA synovium. IL-18 appears to further enhance the Th1 promoting activity of IL-12, an effect which is regulated by IL-18BP.

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Kawashima, M., Missec, P. Effect of IL-18 on synovial cell subsets and its regulation by IL-18BP. Arthritis Res Ther 4 (Suppl 1), 58 (2002).

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