title: IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production.
abstract: Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors: Hao
authors: H
authors: Zhou
authors: Minjia
authors: M
authors: Yu
authors: Koichi
authors: K
authors: Fukuda
authors: Jinteak
authors: J
authors: Im
authors: Peng
authors: P
authors: Yao
authors: Wei
authors: W
authors: Cui
authors: Katarzyna
authors: K
authors: Bulek
authors: Jarod
authors: J
authors: Zepp
authors: Youzhong
authors: Y
authors: Wan
authors: Tae Whan
authors: TW
authors: Kim
authors: Weiguo
authors: W
authors: Yin
authors: Victoria
authors: V
authors: Ma
authors: James
authors: J
authors: Thomas
authors: Jun
authors: J
authors: Gu
authors: Jian-an
authors: JA
authors: Wang
authors: Paul E
authors: PE
authors: DiCorleto
authors: Paul L
authors: PL
authors: Fox
authors: Jun
authors: J
authors: Qin
authors: Xiaoxia
authors: X
authors: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human; C482626:Map3k3 protein, mouse
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