IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production

EMBO J. 2013 Feb 20;32(4):583-96. doi: 10.1038/emboj.2013.2. Epub 2013 Feb 1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • MAP Kinase Kinase Kinase 3 / genetics
  • MAP Kinase Kinase Kinase 3 / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction / physiology*
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / metabolism*

Substances

  • Cytokines
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Interleukin-1
  • TLR7 protein, human
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse
  • MAP Kinase Kinase Kinase 3
  • MAP3K3 protein, human
  • Map3k3 protein, mouse