Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression

Objective. To examine the differential response of rheumatoid arthritis (RA) synovium cell subsets to interleukin-18 (IL-18), the effect of IL-18 on Th1-cytokine production, and the regulation of IL-18 by IL-18 binding protein (IL-1813P). Methods. RA fibroblast-like synoviocytes were stimulated with IL-1beta, IL-12,,and IL-18, and levels of IL-6 were measured by enzyme-linked immunosorbent assay.(ELISA). Expression of IL-18 receptor a and 13 chains (IL-18Ralpha and IL-18Rbeta, respectively), interferon-gamma (IFNgamma), and IL-17 messenger RNA (mRNA) by peripheral blood mononuclear cells, by total RA synovium cells containing T cells obtained after collagenase digestion, and by RA fibroblast-like synoviocytes was determined by reverse transcriptionpolymerase chain reaction. Levels of IFNgamma were measured by ELISA. Results. IL-1beta And, less effectively, IL-12 could induce RA fibroblast-like synoviocytes to produce IL-6, but IL-18 failed to have an effect. Although IL-18Ra mRNA was constitutively expressed by RA fibroblastlike synoviocytes, IL-18Rbeta could not be detected, either with or without stimulation with IL-1 or IL-12. Total RA synovium cells containing T cells showed a strong expression of both IL-18Ralpha and IL-18Rbeta mRNA, and only IL-18Rbeta was up-regulated by IL-12. The combination of IL-12 and IL-18 synergistically up-regulated IFNgamma mRNA expression by total RA synovium cells containing T cells, but down-regulated that of IL-17. IL-12-induced IFNgamma production by total RA synovium cells containing T cells was increased by Additional IL-18 and decreased by IL-18BP. Conclusion. These results indicate that IL-18 plays an important role in RA. inflammation and joint destruction via T cells and macrophages, but it does not have a direct effect on fibroblast-like synoviocytes. IL-18BP may be a tool for RA therapy because of its ability to neutralize endogenous IL-18.