RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IkappaB kinase complex in monocytes.
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.
Department of Molecular Genetics, Microbiology & Immunology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA.
Srijata
S
Sarkar
Junfeng
J
Han
Kristina S
KS
Sinsimer
Baisong
B
Liao
Randi L
RL
Foster
Gary
G
Brewer
Sidney
S
Pestka
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D017931:DNA Primers; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D007370:Interferon Type I; D016753:Interleukin-10; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C000630986:HNRNPD protein, human; C508609:IL10 protein, human