Interleukin-18 (IL-18) is an inflammatory cytokine that has been shown to enhance a variety of Th1 type T cell responses. Because IL-18 is homologous to IL-1, we tested binding of IL-18 to the known IL-1R family members. We could show binding of IL-18 to the orphan receptor IL-1Rrp1 but not to other IL-1R homologous proteins. IL-1Rrp1 and IL-1RI share highly conserved domains within their cytoplasmic regions. Comparison of the IL-1 and IL-18 signaling mechanisms showed that they activate identical cytoplasmic messengers. IL-18, like IL-1, induced association of its receptor with IRAK and subsequent recruitment of TRAF6. IL-18 activated p38 MAP kinase, jun kinase, and beta casein kinase (TIP kinase), an apparently novel kinase previously thought to be specifically activated by IL-1 and tumor necrosis factor (TNF). IL-18 activated NF-kappaB in EL4/6.1 thymoma cells but not in COS-7 cells, even though the latter presumably contain all components required for the IL-1 signaling pathway. From our binding and signaling studies, we conclude that the IL-18 receptor complex consists of IL-18, the IL-1Rrp1, and another thus far unidentified receptor molecule.