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

Youzhong Wan, Hui Xiao, Jeremy Affolter, Tae Whan Kim, Katarzyna Bulek, Sujan Chaudhuri, Deborah Carlson, Thomas Hamilton, Barsanjit Mazumder, George R. Stark, James Thomas, Xiaoxia Li

Research output: Contribution to journalArticle

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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 NFκB 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.

Original languageEnglish (US)
Pages (from-to)10367-10375
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number16
DOIs
StatePublished - Apr 17 2009

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Interleukin-1 Receptor-Associated Kinases
Lipopolysaccharides
Macrophages
Chemokines
Cytokines
Septic Shock
TNF Receptor-Associated Factor 6
Messenger RNA
Phosphorylation
Toll-Like Receptors
Protein Biosynthesis
Mitogen-Activated Protein Kinases
Ribosomes
Bone
Stabilization
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. / Wan, Youzhong; Xiao, Hui; Affolter, Jeremy; Kim, Tae Whan; Bulek, Katarzyna; Chaudhuri, Sujan; Carlson, Deborah; Hamilton, Thomas; Mazumder, Barsanjit; Stark, George R.; Thomas, James; Li, Xiaoxia.

In: Journal of Biological Chemistry, Vol. 284, No. 16, 17.04.2009, p. 10367-10375.

Research output: Contribution to journalArticle

Wan, Y, Xiao, H, Affolter, J, Kim, TW, Bulek, K, Chaudhuri, S, Carlson, D, Hamilton, T, Mazumder, B, Stark, GR, Thomas, J & Li, X 2009, 'Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control', Journal of Biological Chemistry, vol. 284, no. 16, pp. 10367-10375. https://doi.org/10.1074/jbc.M807822200
Wan, Youzhong ; Xiao, Hui ; Affolter, Jeremy ; Kim, Tae Whan ; Bulek, Katarzyna ; Chaudhuri, Sujan ; Carlson, Deborah ; Hamilton, Thomas ; Mazumder, Barsanjit ; Stark, George R. ; Thomas, James ; Li, Xiaoxia. / Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 16. pp. 10367-10375.
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