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Nat Immunol. 2005 Aug;6(8):777-84. Epub 2005 Jul 10.

Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.

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  • 1Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2170, USA. michmart@uab.edu

Abstract

The cellular mechanisms that directly regulate the inflammatory response after Toll-like receptor (TLR) stimulation are unresolved at present. Here we report that glycogen synthase kinase 3 (GSK3) differentially regulates TLR-mediated production of pro- and anti-inflammatory cytokines. Stimulation of monocytes or peripheral blood mononuclear cells with TLR2, TLR4, TLR5 or TLR9 agonists induced substantial increases in interleukin 10 production while suppressing the release of proinflammatory cytokines after GSK3 inhibition. GSK3 regulated the inflammatory response by differentially affecting the nuclear amounts of transcription factors NF-kappaB subunit p65 and CREB interacting with the coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response.

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PMID:
16007092
[PubMed - indexed for MEDLINE]
PMCID:
PMC1933525
Free PMC Article

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