Abstract
Inflammatory stimulants such as bacterial endotoxin (lipopolysaccharide (LPS)) are known to induce tissue damage and injury partly through the induction of reactive oxygen species (ROS). Although it is recognized that the induction of ROS in macrophages by LPS depends upon the expression and activation of NADPH oxidase, as well as the suppression of antioxidative enzymes involved in ROS clearance, the underlying molecular mechanisms are poorly defined. In this study, we examined the contribution of the interleukin-1 receptor-associated kinase 1 (IRAK-1) to LPS-induced generation of ROS. We observed that LPS induced significantly less ROS in IRAK-1(-/-) macrophages, indicating that IRAK-1 is critically involved in the induction of ROS. Mechanistically, we observed that IRAK-1 is required for LPS-induced expression of NOX-1, a key component of NADPH oxidase, via multiple transcription factors, including p65/RelA, C/EBPbeta, and C/EBPdelta. On the other hand, we demonstrated that IRAK-1 associated with and activated small GTPase Rac1, a known activator of NOX-1 oxidase enzymatic activity. IRAK-1 forms a close complex with Rac1 via a novel LWPPPP motif within the variable region of IRAK-1. On the other hand, we also observed that IRAK-1 is required for LPS-mediated suppression of peroxisome proliferator-activated receptor alpha and PGC-1alpha, nuclear factors essential for the expression of antioxidative enzymes such as GPX3 and catalase. Consequently, injection of LPS causes significantly less plasma lipid peroxidation in IRAK-1(-/-) mice compared with wild type mice. Taken together, our study reveals IRAK-1 as a novel component involved in the generation of ROS induced by LPS.