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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Regulation of IL-1 receptor-associated kinases by lipopolysaccharide.

IL-1R-associated kinase ( IRAK) plays a pivotal role in IL-1R/Toll-like receptor (TLR)- mediated signaling and NF-kappaB activation. IRAK from leukocytes undergoes rapid activation and inactivation/degradation following IL-1 or LPS stimulation. The rapid degradation of IRAK may serve as a negative feedback mechanism of down-regulating IL-1R/TLR-mediated signaling and cytokine gene transcription. Although IL-1/IL-1R- triggered IRAK degradation has been studied in detail, the mechanism of LPS- induced IRAK activation and degradation is not clearly defined. In this study, we demonstrate that the IRAK N-terminal 186-aa region is required for LPS-induced degradation. The N-terminally truncated IRAK protein expressed in human monocytic THP-1 cells remains stable upon LPS challenge. In comparison, IRAK as well as the IRAK mutant with C-terminal truncation undergo degradation with LPS stimulation. We demonstrate that pretreatment with protein kinase C inhibitor calphostin inhibits LPS- induced IRAK degradation. Furthermore, we observe coimmunoprecipitation of endogenous IRAK and protein kinase C-zeta protein. We show that functional TLR4 is required for LPS- mediated IRAK degradation. IRAK protein in the murine GG2EE cells harboring a mutated TLR4 gene does not undergo degradation upon LPS treatment. In sharp contrast, we observe that the IRAK homolog, IRAK2, does not undergo degradation upon prolonged LPS treatment, suggesting complex regulation of the innate immunity network upon microbial challenge.[1]


  1. Regulation of IL-1 receptor-associated kinases by lipopolysaccharide. Hu, J., Jacinto, R., McCall, C., Li, L. J. Immunol. (2002) [Pubmed]
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