To investigate the presence and role of interleukin-17 (IL-17) in rheumatoid arthritis (RA), and its regulation by antiinflammatory cytokines. The production of IL-17 was measured in supernatants of RA, osteoarthritis (OA), and normal synovial tissue pieces cultured ex vivo. Quantification of IL-17 was performed using a specific biologic assay. IL-17 gene expression was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR)-techniques. Immunohistochemistry was used to evaluate the frequency of IL-17-positive cells in synovium. The secretion of IL-17 by synovium was measured in the presence of IL-4, IL-13, and IL-10. In addition, the contributions of exogenous and endogenous IL-17 to IL-6 production by RA synovium were studied. Functional IL-17 was spontaneously produced by 16 of 18 RA (mean +/- SEM 41.7+/-11.4 units/ml), 2 of 12 OA (5.3+/-4.5 units/ml), and 0 of 3 normal synovial explant cultures. IL-17 messenger RNA expression was demonstrated by RT-PCR in 4 of 5 RA and 0 of 3 OA synovial samples. By immunostaining of RA synovium, IL-17-producing cells were found in the T cell-rich area. Addition of both IL-4 and IL-13 completely inhibited the production of IL-17, whereas IL-10 had no effect. Addition of exogenous IL-17 to RA synovium resulted in an increase in IL-6 production, whereas that of a blocking anti-IL-17 antibody reduced production of IL-6. The T cell cytokine IL-17 was found to be highly produced by RA, but not by OA, synovium. Its production and function were down-regulated by IL-4 and IL-13. These results indicate that IL-17 contributes to the active, proinflammatory pattern that is characteristic of RA. Through the contribution of IL-17, some Th1-like T cells appear to mediate synovial inflammation.