Interleukin-1 Receptor-associated Kinase 2 Is Critical for Lipopolysaccharide-mediated Post-transcriptional Control

Abstract

IRAK2, a member of the interleukin-1 receptor-associated kinase (IRAK) family, has been implicated in Toll-like receptor (TLR)-mediated signaling. We generated IRAK2-deficient mice to examine its function in detail. These mice are resistant to lipopolysaccharide-induced septic shock, because of impaired TLR4-mediated induction of pro-inflammatory cytokines and chemokines. Although IRAK2 deficiency did not affect TLR4-mediated NFB activation, a reduction of lipopolysaccharide (LPS)-mediated mRNA stabilization contributed to the reduced cytokine and chemokine production observed in bone marrow-derived macrophages from IRAK2-deficient mice. Furthermore, the ratios of LPS-induced cytokine and chemokine mRNAs in translation-active (polysomal) versus translation-inactive (free ribosomes) pools were reduced in IRAK2-deficient macrophages compared with wild type macrophages. Importantly, LPS-induced phosphorylation of MKK3/6, MNK1, and eIF4E was significantly reduced in IRAK2-deficient macrophages compared with wild type macrophages. Moreover, LPS stimulation induced an interaction of IRAK2 with TRAF6, MKK3/6, and MK2, implicating a critical role for mitogen-activated protein kinase signaling in LPS-induced IRAK2-mediated post-transcriptional control. These results reveal that IRAK2 is required for LPS-mediated post-transcriptional control of cytokine and chemokine expression, which plays an essential role in TLR4-induced septic shock.

The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling

“…Similar results were shown for TLR7 signalling to NFκB by a separate group using independently generated IRAK-2 -/-mice (63). Only when IRAK-2 -/-mice were crossed with IRAK-1 -/-mice was a dramatic impairment of NFκB activation by TLR2 observed…”

“…PBMCs that were deficient in IRAK-4 failed to respond to stimulation with TLR7/8 agonists, and no IFNα, IFNβ and IFN λ mRNA or protein was induced in these cells (61). In contrast, normal p38, JNK, (63). While it was shown, using IRAK-2 -/-macrophages that murine IRAK-2 has no role in TLR4-induced early or 26 sustained NFκB activation, TLR-4 induced cytokines and chemokine production was greatly affected since TLR4-induced stability of IL-6 and KC mRNA was shown to be regulated by IRAK-2 (63).…”

MyD88 Adaptor-Like Is Not Essential for TLR2 Signaling and Inhibits Signaling by TLR3

“…The interaction of TLR3 directly with IRAK2 has previously been shown to be crucial for TLR3 signaling (34). IRAK2 has also recently been shown to be important for TLR4-mediated mRNA stabilization and translational control in macrophages (35). It was shown that IRAK2 can form complexes with several MAPK kinases and TRAF6 upon TLR4 activation.…”

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

“…These data suggest that IRAK-1 and IRAK-2 play mutually redundant roles, at least downstream from IL-1R, in human fibroblasts. Mouse studies have shown that IRAK-2 is crucial for cytokine production by bone marrowderived macrophages in response to TLR4 stimulation (17,39). Similarly, IRAK-2 has been shown to be essential for the LPSinduced response of human HEK-293 cells and human PBMCs (107).…”

“…IL-1R/TLR signaling was not assessed in Irak2 −/− and Irak3 −/− splenocytes. In vivo studies have shown survival to be higher for Irak1 −/− , Irak2 −/− , and Irak4 −/− mice following LPS injection (Irak3 −/− mice were not tested) (11,38,39) and lower for Irak1 −/− and Irak4 −/− mice (the only two strains tested) following Staphylococcus aureus infection (11,40). Myd88 −/− mice and, by inference, Irak4 −/− mice are susceptible to many other pathogens not used for the inoculation of the other mutants (41).…”