TLR3 - Published April 30, 2007 ARTICLE A critical role for...

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The Journal of Experimental Medicine ARTICLE JEM © The Rockefeller University Press $15.00 Vol. 204, No. 5, May 14, 2007 1025–1036 1025 Innate immunity is the f rst line oF deFense against pathogenic microorganisms. Toll-like receptors (TLRs) (1–6) play a critical role in innate immune responses in mammals through the recognition oF conserved molecular patterns associated with di± erent microorganisms. Although TLR4 has been genetically identif ed as a signaling mole- cule essential For the responses to LPS, a com- ponent oF gram-negative bacteria (7), TLR2 responds to mycobacteria, yeast, and gram- positive bacteria (8–11). TLR6 associates with TLR2 and recognizes lipoproteins From mico- plasma. TLR5 and TLR9 mediates the induc- tion oF the immune response by bacterial ² agellins (12) and bacterial DNA (5), respectively. Although TLR3 recognizes double-stranded RNA (13), single-stranded RNA is the natural ligand For TLR7/8 (14, 15). The natural ligands For TLR10 and TLR11 are still not known (6). Upon binding oF TLR ligands, all oF the TLRs except TLR3 recruit the adaptor molecule MyD88 through the TIR domain, mediating the so-called MyD88-dependent pathway (16). MyD88 then recruits serine-threonine kinases IL-1R–associated kinase (IRAK)4 (17–19) and IRAK (20, 21). Although IRAK4 is the kinase that Functions upstream oF and phos- phorylates IRAK, the phosphorylated IRAK mediates the recruitment oF TRA³6 to the re- ceptor complex (22). Upon phosphorylation oF IRAK, the IRAK–TRA³6 complex dissoci- ates From the receptor complex to interact with and activate TG³- β –activated kinase 1 (TAK1), a member oF the mitogen-activated protein ki- nase kinase kinase Family (23). The activation oF TAK1 eventually leads to the activation oF N³- κ B and c-Jun NH 2 -terminal kinase (JNK) (24), resulting in induction oF in² ammatory cyto- kines and chemokines such as TN³- α , IL-1 β , IL-6, and IL-8. Recent studies have begun to unravel how a subset oF TLRs, TLR7, TLR8, and TLR9 use a novel MyD88-dependent pathway to mediate the activation oF transcription Factors A critical role for IRAK4 kinase activity in Toll-like receptor–mediated innate immunity Tae Whan Kim, 1,4 Kirk Staschke, 3 Katarzyna Bulek, 1 Jianhong Yao, 1 Kristi Peters, 2 Keun-Hee Oh, 1 Yvonne Vandenburg, 3 Hui Xiao, 1 Wen Qian, 1 Tom Hamilton, 1 Booki Min, 1 Ganes Sen, 2 Raymond Gilmour, 3 and Xiaoxia Li 1 1 Department of Immunology, 2 Department of Molecular Genetics, Cleveland Clinic Foundation, 3 Lilly Research Laboratories, Indianapolis, 46285 IN 4 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 IRAK4 is a member of IL-1 receptor (IL-1R)–associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)–mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase–inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinF ammatory cytokines and chemokines. Although inactiva-
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TLR3 - Published April 30, 2007 ARTICLE A critical role for...

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