Functional maturation of T cells towards a Th1 or Th2 phenotype has important implications in the generation and perpetuation of autoimmune responses. Those factors that promote and sustain Th1 responses in rheumatoid arthritis (RA) are unclear. We are currently exploring the functional effects of the predominantly macrophage-derived cytokines, IL-12, IL-15 and IL-18, on synovial T cells. We have previously shown a role for IL-15 in synovial T cell chemokinesis and in TNFα production through promotion of cytokine-mediated T cell/macrophage cell contact. We have now extended these studies to include IL-12 and IL-18. IL-18 mRNA and protein may be detected by RT-PCR, ELISA, and immunohistochemistry in RA synovial membrane. The absolute levels present vary considerably between patients. In synergy with IL-12 and IL-15, IL-18 induces high levels of IFNγ, TNFα, and GM-CSF production. IL-18 mediates effects directly on synovial T cells and macrophages. IL-18 and IL-15 expression is itself enhanced by IL-1β/TNFα in vitro, suggesting the existence of feedback loops that provide reciprocal amplification of Th1 cells and monokine production within the synovial membrane. These data clearly indicate that synergistic combinations of T cell activatory cytokines can promote synovial inflammation. This has important implications for the choice of therapeutic targets designed to suppress Th1 cell activity in autoimmune lesions.