IL-1 receptor-associated kinase modulates host responsiveness to endotoxin

Endotoxin triggers many of the inflammatory, hemodynamic, and hematological derangements of Gram-negative septic shock. Recent genetic studies in mice have identified the Toll-like receptor 4 as the transmembrane endotoxin si gnal transducer. The IL-1 intracellular signaling pathway has been implicat ed in Toll-like receptor signal transduction. LPS-induced activation of the IL-1 receptor-associated kinase (IRAK), and the influence of IRAK on intra cellular signaling and cellular responses to endotoxin has not been explore d in relevant innate immune cells. We demonstrate that LPS activates IRAK i n murine macrophages, IRAK-deficient macrophages, in contrast, are resistan t to LPS. Deletion of IRAK disrupts several endotoxin-triggered signaling c ascades. Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimula ted TNF-alpha production, and IRAK-deficient mice withstand the lethal effe cts of LPS, These findings, coupled with the critical role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the importance of this kinase a nd the IL-1/Toll signaling cassette in sensing and responding to Gram-negat ive infection.