The EMBO journal, 2013-02, Vol.32 (4), p.583-596
2013
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Details
- Autor(en) / Beteiligte
- Titel
- IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production
- Ist Teil von
- The EMBO journal, 2013-02, Vol.32 (4), p.583-596
- Ort / Verlag
- Chichester, UK: John Wiley & Sons, Ltd
- Erscheinungsjahr
- 2013
- Quelle
- Wiley Online Library All Journals
- Beschreibungen/Notizen
- 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. IRAK‐M was reported to inhibit TLR signalling. Now, IRAK‐M is shown to activate NFκB via interaction with MyD88/IRAK‐4 leading to the induction of a negative feedback loop that limits the inflammatory response.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0261-4189eISSN: 1460-2075DOI: 10.1038/emboj.2013.2Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3579143
- Format
- –
- Schlagworte
- Animals, Cell Line, Cytokines - biosynthesis, Cytokines - genetics, Humans, Interleukin-1 Receptor-Associated Kinases - genetics, Interleukin-1 Receptor-Associated Kinases - metabolism, IRAK, MAP Kinase Kinase Kinase 3 - genetics, MAP Kinase Kinase Kinase 3 - metabolism, Membrane Glycoproteins - genetics, Membrane Glycoproteins - metabolism, Mice, myddosome, NF-kappa B - genetics, NF-kappa B - metabolism, Receptors, Interleukin-1 - genetics, Receptors, Interleukin-1 - metabolism, Signal Transduction - physiology, signalling, Toll-like receptor, Toll-Like Receptor 7 - genetics, Toll-Like Receptor 7 - metabolism