期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 31, 期 4, 页码 602-615出版社
TAYLOR & FRANCIS INC
DOI: 10.1128/MCB.00835-10
关键词
-
资金
- NIH, NIAID [P01 AI057596, R01 AI059465, T32 AI00743]
- NIH, NCI [R01 CA052443]
Exposure of monocytes and macrophages to endotoxin/lipopolysaccharide (LPS) from Gram-negative bacteria activates the NF-kappa B 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-kappa B signaling, and the expression of an RNA interference-refractory p40(AUF1) cDNA restores both signaling pathways. To define the molecular mechanisms by which p40(AUF1) controls IL10 expression, we focused on the NF-kappa B pathway in search of AUF1-regulated targets. Here, we show that p40(AUF1) serves to maintain proper levels of the kinase TAK1 (transforming growth factor-beta-activated kinase), which phosphorylates the IKK beta subunit within the I kappa B kinase complex to activate NF-kappa B-regulated genes. However, p40(AUF1) does not control the TAK1 mRNA levels but instead promotes the translation of the mRNA. Thus, p40(AUF1) regulates a critical node within the NF-kappa B signaling pathway to permit IL10 induction for the anti-inflammatory arm of an innate immune response.
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