RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IκB kinase complex in monocytes

Srijata Sarkar, Junfeng Han, Kristina S. Sinsimer, Baisong Liao, Randi L. Foster, Gary Brewer, Sidney Pestka

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Exposure of monocytes and macrophages to endotoxin/lipopolysaccharide (LPS) from Gram-negative bacteria activates the NF-κB signaling pathway. At early times, this leads to their production of proinflammatory cytokines, but subsequently, they produce anti-inflammatory interleukin-10 (IL-10) to quell the immune response. LPS-mediated induction of IL10 gene expression requires the p40 isoform of the RNA-binding protein AUF1. As LPS exerts modest effects upon IL10 mRNA stability, we hypothesized that AUF1 controls the expression of signaling proteins. Indeed, knockdown of AUF1 impairs LPS-mediated p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling, and the expression of an RNA interference-refractory p40AUF1 cDNA restores both signaling pathways. To define the molecular mechanisms by which p40 AUF1 controls IL10 expression, we focused on the NF-κB pathway in search of AUF1-regulated targets. Here, we show that p40AUF1 serves to maintain proper levels of the kinase TAK1 (transforming growth factor-β-activated kinase), which phosphorylates the IKKβ subunit within the IκB kinase complex to activate NF-κB-regulated genes. However, p40AUF1 does not control the TAK1 mRNA levels but instead promotes the translation of the mRNA. Thus, p40AUF1 regulates a critical node within the NF-κB signaling pathway to permit IL10 induction for the anti-inflammatory arm of an innate immune response.

Original languageEnglish (US)
Pages (from-to)602-615
Number of pages14
JournalMolecular and cellular biology
Volume31
Issue number4
DOIs
StatePublished - Feb 1 2011

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RNA-Binding Proteins
Interleukin-10
Lipopolysaccharides
Monocytes
Phosphotransferases
Anti-Inflammatory Agents
Proto-Oncogene Proteins c-akt
RNA Stability
Protein Biosynthesis
Transforming Growth Factors
p38 Mitogen-Activated Protein Kinases
RNA Interference
Gram-Negative Bacteria
Innate Immunity
Endotoxins
Protein Isoforms
Complementary DNA
Macrophages
Cytokines
Gene Expression

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Sarkar, Srijata ; Han, Junfeng ; Sinsimer, Kristina S. ; Liao, Baisong ; Foster, Randi L. ; Brewer, Gary ; Pestka, Sidney. / RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IκB kinase complex in monocytes. In: Molecular and cellular biology. 2011 ; Vol. 31, No. 4. pp. 602-615.
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RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IκB kinase complex in monocytes. / Sarkar, Srijata; Han, Junfeng; Sinsimer, Kristina S.; Liao, Baisong; Foster, Randi L.; Brewer, Gary; Pestka, Sidney.

In: Molecular and cellular biology, Vol. 31, No. 4, 01.02.2011, p. 602-615.

Research output: Contribution to journalArticle

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