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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 NFkappaB 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.

SUBMITTER: Wan Y

PROVIDER: S-EPMC2667724 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control.

Wan Youzhong Y Xiao Hui H Affolter Jeremy J Kim Tae Whan TW Bulek Katarzyna K Chaudhuri Sujan S Carlson Deborah D Hamilton Thomas T Mazumder Barsanjit B Stark George R GR Thomas James J Li Xiaoxia X

The Journal of biological chemistry 20090218 16

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 NFkappaB activation, a reduction of lipopolysaccharide (LPS)-mediated ...[more]

PMID: 19224918

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Project description:The post-receptor pathway that leads to nuclear factor kappaB (NF-kappaB) activation begins with the assembly of a membrane-proximal complex among the interleukin 1 (IL-1) receptors and the adaptor molecules, myeloid differentiation protein 88 (MyD88), IL-1-receptor-associated kinases (IRAKs) and tumour-necrosis-factor-receptor-associated factor 6. Eventually, phosphorylation of the inhibitor of NF-kappaB (IkappaB) by the IkappaB kinases releases NF-kappaB, which translocates to the nucleus and modulates gene expression. In this paper, we report that IRAK2 and MyD88, but not IRAK1, interact physically with Akt, as demonstrated by co-immunoprecipitation and pull-down experiments. Interestingly, the association of Akt with recombinant IRAK2 is decreased by stimulation with IL-1, and is favoured by pre-treatment with phosphatase. Likewise, Akt association with IRAK2 is increased considerably by overexpression of PTEN (phosphatase and tensin homologue deleted on chromosome 10), while it is completely abrogated by overexpression of phosphoinositide-dependent protein kinase 1. These data indicate that Akt takes part in the formation of the signalling complex that conveys the signal from the IL-1 receptors to NF-kappaB, a step that is much more membrane-proximal than was reported previously. We also demonstrate that Akt activity is necessary for IL-1-dependent NF-kappaB transactivation, since a kinase-defective mutant of Akt impairs IRAK2- and MyD88-dependent, but not IRAK1-dependent, NF-kappaB activity, as monitored by a gene reporter assay. Accordingly, IRAK2 failed to trigger inducible nitric oxide synthase and IL-1beta production in cells expressing dominant-negative Akt. However, NF-kappaB binding to DNA was not affected by inhibition of Akt, indicating that Akt regulates NF-kappaB at a level distinct from the dissociation of p65 from IkappaBalpha and its translocation to the nucleus, possibly involving phosphorylation of the p65 transactivation domain.

Dataset Information

Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control.

Publications

Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control.

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