Mature form of interleukin 18 is expressed in rheumatoid arthritis synovial tissue and contributes to interferon-γ production by synovial T cells

Objective. To investigate the expression and function of interleukin 18 (IL-18) in synovial tissue (ST) of patients with rheumatoid arthritis (RA). Methods. The localization of IL-18 in ST was analyzed by immunohistochemistry. IL-18 and IL-18 receptor (IL-18R)mRNA were detected by RT-PCR. Expression of IL-18 at the protein level was analyzed by Western blotting. Cytokines in culture supernatants were measured by ELISA. Results. From immunohistochemical analysis, IL-18-producing cells were localized in the lining layer and sublining region of RA ST. Most of them coexpressed CD68 antigen. In ST from patients with osteoarthritis (OA), IL-18-producing cells were localized only in the sublining region and the numbers of these cells were small. From RT-PCR, RA ST expressed mRNA of IL-18, as well as alpha -and beta -chains of IL-18R. OA ST did not express or very weakly expressed mRNA of alpha- and beta -chains of IL-18R. ST from RA patients produced significantly larger amounts of IL-18 in vitro than OA ST. Western blotting revealed that RA ST expressed mature IL-18 more abundantly than OA ST. IL-12 alone stimulates interferon-gamma (IFN-gamma) production by RA synovial tissue cells, but IL-18 alone could not. In the presence of IL-12, however, IL-18 could synergistically stimulate IFN-gamma production by RA synovial tissue cells. OA synovial tissue cells responded to neither IL-12 nor IL-12 + IL-18. IL-18 showed synergistic effects with IL-12 on promoting the ability of synovial T cells from RA patients to produce IFN-gamma. Conclusion. These findings suggest that mature IL-18 is expressed in RA synovia and contributes to the production of IFN-gamma by infiltrating T cells.