Toll-like-receptor (TLR) mediated innate immunity signaling regulates various aspects of inflammation processes. Activations of TLRs lead to diverse gene expressions mediated by various transcription factors including NFkB, IRFs, as well as Stats. The specific regulatory mechanism leading to differential activation of distinct transcription is not clearly understood. Studies from others as well as our lab indicate that interleukin-1 receptor associate kinase 1 (IRAK1) is a key signaling molecule in the TLR mediated innate immunity signaling pathway. Although IRAK1 is currently thought to be a proximal signaling molecule playing a somewhat redundant role together with IRAK4 in activating NFkB, IRAK1 knockout mice still retain IPS inducible NFkB activation. Our recent study using IRAK1 deficient mice indicates that IRAK1 is playing a novel role in activating the transcription factor Stat3 and subsequently responsible for IL-10 gene expression. Strikingly, we also found that ubiquitinated IRAK1 enters nucleus upon IPS challenge and directly binds with endogenous IL-10 promoter element as determined by chromatin immunoprecipitation assay. This raises a novel issue of IRAK1 serving directly as a transcriptional regulator besides functioning as a conventional proximal signaling molecule. Furthermore, we have observed that IRAK1 is consistently ubiquitinated and distributed in the nucleus of peripheral blood mononuclear cells from atherosclerosis patients, correlating with the elevated serum IL-10 levels. Elevated IL-10 may be a self-protective mechanism preventing excessive inflammation during atherosclerosis. With these novel findings, we hypothesize that IRAK1 is uniquely positioned in the TLR signaling pathway to specifically activate Stat3. The objective of this grant is to further characterize, at the biochemical level, how IRAK1 is critically involved in Stat3 activation and IL-10 gene expression. Furthermore, since IRAK1 is consistently ubiquitinated in atherosclerosis patient, we hypothesize that IRAK1 may be intimately involved in either the pathogenesis or resolution of atherosclerosis.
Aim 1 will address the mechanism of IRAK1 ubiquitination, nuclear entry, and interaction with Stat3.
Aim2 will examine the mechanism for IRAK1 mediated IL-10 gene expression.
Aim3 will study the effect of IRAK1 deletion on the pathogenesis and/or resolution of atherosclerosis.
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