RNA-Binding Protein AUF1 Regulates Lipopolysaccharide-Induced IL10 Expression by Activating IκB Kinase Complex in Monocytes

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 p40^AUF1 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 p40^AUF1 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, 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-κB signaling pathway to permit IL10 induction for the anti-inflammatory arm of an innate immune response.

ACKNOWLEDGMENTS

This work was supported by grants P01 AI057596 from the NIH, NIAID, to S.P., R01 AI059465 from the NIH, NIAID, to S.P., and R01 CA052443 from the NIH, NCI, to G.B. K.S.S. was supported by training grant T32 AI00743 from the NIH, NIAID, to S.P.

We have no conflicting financial interests.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00835-10.