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

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.

Pubmed ID: 19224918 RIS Download

Mesh terms: Animals | Bone Marrow Cells | Chemokines | Cytokines | Gene Expression Regulation | Interleukin-1 Receptor-Associated Kinases | Lipopolysaccharides | MAP Kinase Signaling System | Macrophages | Mice | Mice, Inbred C57BL | Mice, Knockout | Mitogen-Activated Protein Kinases | NF-kappa B | Protein Biosynthesis | RNA Processing, Post-Transcriptional | RNA Stability | Toll-Like Receptor 4 | Transcription, Genetic

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM060020
  • Agency: NIGMS NIH HHS, Id: P50 GM021681
  • Agency: NIAID NIH HHS, Id: R01 AI50019
  • Agency: NHLBI NIH HHS, Id: R01 HL 79164

Mouse Genome Informatics (Data, Gene Annotation)

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