| First Author | Bruni D | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 6 | Pages | 2844-56 |
| PubMed ID | 23396947 | Mgi Jnum | J:193597 |
| Mgi Id | MGI:5468846 | Doi | 10.4049/jimmunol.1202042 |
| Citation | Bruni D, et al. (2013) A Novel IRAK1-IKK{varepsilon} Signaling Axis Limits the Activation of TAK1-IKKbeta Downstream of TLR3. J Immunol 190(6):2844-56 |
| abstractText | 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-kappaB pathway. Following TLR3 stimulation, IRAK1-deficient macrophages produced increased levels of IL-6 and IFN-beta compared with wild type macrophages. Pharmacological inhibition of TAK1 reduced this increase in IFN-beta, together with the heightened activation of IRF3 and p65 found in TLR3-ligand stimulated IRAK1-deficient macrophages. Recently, IKKepsilon and TANK-binding kinase 1 (TBK1) were reported to limit activation of the NF-kappaB pathway downstream of IL-1R, TNFR1, and TLRs. We show that TBK1 has a positive role in the TLR3-NF-kappaB pathway, because we detected reduced levels of IL-6 and reduced activation of p65 in TBK1-deficient macrophages. In contrast, we show that IKKepsilon limits the activation of the TLR3-NF-kappaB pathway. Furthermore, we show that IRAK1 is required for the activation of IKKepsilon downstream of TLR3. We report impaired activation of ERK1/2 in IRAK1- and IKKepsilon-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-IKKepsilon-signaling axis acts to limit the production of both type I IFNs and proinflammatory cytokines by regulating TAK1 activity. |
