The interleukin-1 receptor (IL-1R) signaling pathway leads to nuclear factor kappa B (NF-kappa B) activation in mammals and is similar to the Toll pathway in Drosophila : the IL-1R-associated kinase (IRAK) is homologous to Pelle. Two additional proximal mediators were identified that are required for IL-1R-induced NF-kappa B activation : IRAK-2, a Pelle family member, and MyD88, a death domain-containing adapter molecule. Both associate with the IL-IR signaling complex. Dominant negative forms of either attenuate IL-1R-mediated NF-kappa B activation. Therefore, IRAK-2 and MyD88 may provide additional therapeutic targets for inhibiting IL-1-induced inflammation.