| First Author | Pauls E | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 5 | Pages | 2717-30 |
| PubMed ID | 23918981 | Mgi Jnum | J:205798 |
| Mgi Id | MGI:5546465 | Doi | 10.4049/jimmunol.1203268 |
| Citation | Pauls E, et al. (2013) Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice. J Immunol 191(5):2717-30 |
| abstractText | The roles of IL-1R-associated kinase (IRAK)2 and IRAK1 in cytokine production were investigated using immune cells from knock-in mice expressing the TNFR-associated factor 6 (TRAF6) binding-defective mutant IRAK2[E525A] or the catalytically inactive IRAK1[D359A] mutant. In bone marrow-derived macrophages (BMDMs), the IRAK2-TRAF6 interaction was required for the late (2-8 h) but not the early phase (0-2 h) of il6 and tnfa mRNA production, and hence for IL-6 and TNF-alpha secretion by TLR agonists that signal via MyD88. Loss of the IRAK2-TRAF6 interaction had little effect on the MyD88-dependent production of anti-inflammatory molecules produced during the early phase, such as Dual Specificity Phosphatase 1, and a modest effect on IL-10 secretion. The LPS/TLR4-stimulated production of il6 and tnfa mRNA and IL-6 and TNF-alpha secretion was hardly affected, because the Toll/IL-1R domain-containing adapter-inducing IFN-beta (TRIF) signaling pathway was used instead of the IRAK2-TRAF6 interaction to sustain late-phase mRNA production. IRAK1 catalytic activity was not rate limiting for il6, tnfa, or il10 mRNA production or the secretion of these cytokines by BMDMs, but IFN-beta mRNA induction by TLR7 and TLR9 agonists was greatly delayed in plasmacytoid dendritic cells (pDCs) from IRAK1[D359A] mice. In contrast, IFN-beta mRNA production was little affected in pDCs from IRAK2[E525A] mice, but subsequent IFN-alpha mRNA production and IFN-alpha secretion were reduced. IFN-beta and IFN-alpha production were abolished in pDCs from IRAK1[D359A] x IRAK2[E525A] double knock-in mice. Our results establish that the IRAK2-TRAF6 interaction is rate limiting for the late, but not the early phase of cytokine production in BMDM and pDCs, and that the IRAK2-TRAF6 interaction is needed to sustain IkappaB-inducing kinase beta activity during prolonged activation of the MyD88 signaling network. [corrected] |
