title: A novel IRAK1-IKKε signaling axis limits the activation of TAK1-IKKβ downstream of TLR3.
abstract: IRAK1 is involved in the regulation of type I IFN production downstream of TLR3. Previous work indicated that IRAK1 negatively regulates TRIF-mediated activation of IRF3 and IRF7. We report that IRAK1 limits the activation of the TLR3-NF-κB pathway. Following TLR3 stimulation, IRAK1-deficient macrophages produced increased levels of IL-6 and IFN-β compared with wild type macrophages. Pharmacological inhibition of TAK1 reduced this increase in IFN-β, together with the heightened activation of IRF3 and p65 found in TLR3-ligand stimulated IRAK1-deficient macrophages. Recently, IKKε and TANK-binding kinase 1 (TBK1) were reported to limit activation of the NF-κB pathway downstream of IL-1R, TNFR1, and TLRs. We show that TBK1 has a positive role in the TLR3-NF-κB pathway, because we detected reduced levels of IL-6 and reduced activation of p65 in TBK1-deficient macrophages. In contrast, we show that IKKε limits the activation of the TLR3-NF-κB pathway. Furthermore, we show that IRAK1 is required for the activation of IKKε downstream of TLR3. We report impaired activation of ERK1/2 in IRAK1- and IKKε-deficient macrophages, a novel finding for both kinases. Importantly, this work provides novel mechanistic insight into the regulation of the TLR3-signaling pathway, providing strong evidence that an IRAK1-IKKε-signaling axis acts to limit the production of both type I IFNs and proinflammatory cytokines by regulating TAK1 activity.
authors: Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.
authors: Daniela
authors: D
authors: Bruni
authors: Jordi
authors: J
authors: Sebastia
authors: Susan
authors: S
authors: Dunne
authors: Martina
authors: M
authors: Schröder
authors: Marion P
authors: MP
authors: Butler
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D017628:Microglia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D025941:Protein Interaction Mapping; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D035602:Transcriptional Elongation Factors; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002352:Carrier Proteins; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D051196:Toll-Like Receptor 3; D035602:Transcriptional Elongation Factors; D000099151:MAP Kinase Kinase Kinase 7; C114720:Elp1 protein, human; C491968:Ikbkap protein, mouse; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; C507768:IRAK1 protein, human