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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


  • Wan Y
  • Xiao H
  • Affolter J
  • Kim TW
  • Bulek K
  • Chaudhuri S
  • Carlson D
  • Hamilton T
  • Mazumder B
  • Stark GR
  • Thomas J
  • Li X


The Journal of biological chemistry

Publication Data

April 17, 2009

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

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