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IRAK‐M mediates Toll‐like receptor/IL‐1R‐induced NFκB activation and cytokine production
Author(s) -
Zhou Hao,
Yu Minjia,
Fukuda Koichi,
Im Jinteak,
Yao Peng,
Cui Wei,
Bulek Katarzyna,
Zepp Jarod,
Wan Youzhong,
Whan Kim Tae,
Yin Weiguo,
Ma Victoria,
Thomas James,
Gu Jun,
Wang Jianan,
DiCorleto Paul E,
Fox Paul L,
Qin Jun,
Li Xiaoxia
Publication year - 2013
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2013.2
Subject(s) - biology , chemokine , microbiology and biotechnology , tlr7 , nf κb , signal transduction , cytokine , receptor , signal transducing adaptor protein , toll like receptor , innate immune system , immunology , biochemistry
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.