Journal
JOURNAL OF IMMUNOLOGY
Volume 191, Issue 5, Pages 2717-2730Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203268
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Funding
- Wellcome Trust Senior Investigator Award
- U.K. Medical Research Council
- AstraZeneca
- Boehringer-Ingelheim
- GlaxoSmithKline
- Janssen Pharmaceutica
- Merck-Serono
- Pfizer
- MRC [MC_EX_G0800765, MR/K000985/1, MC_UU_12016/11, MC_U127084348, MC_EX_UU_G0800765] Funding Source: UKRI
- Medical Research Council [MC_U127084348, MR/K000985/1, MC_EX_UU_G0800765, MC_UU_12016/11, MC_EX_G0800765] Funding Source: researchfish
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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] 3 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 I kappa B-inducing kinase beta activity during prolonged activation of the MyD88 signaling.
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