Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3
Top Cited Papers
Open Access
- 10 July 2005
- journal article
- research article
- Published by Springer Nature in Nature Immunology
- Vol. 6 (8) , 777-784
- https://doi.org/10.1038/ni1221
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-κB 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.Keywords
This publication has 51 references indexed in Scilit:
- Glycogen Synthase Kinase-3β Regulates NF-κB1/p105 StabilityJournal of Biological Chemistry, 2003
- PI3K-mediated negative feedback regulation of IL-12 production in DCsNature Immunology, 2002
- The Phosphoinositide 3-Kinase PathwayScience, 2002
- TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophagesNature Immunology, 2002
- Signaling by Toll-Like Receptor 2 and 4 Agonists Results in Differential Gene Expression in Murine MacrophagesInfection and Immunity, 2001
- Phosphorylation of NF-κB p65 by PKA Stimulates Transcriptional Activity by Promoting a Novel Bivalent Interaction with the Coactivator CBP/p300Molecular Cell, 1998
- NF-κB AND REL PROTEINS: Evolutionarily Conserved Mediators of Immune ResponsesAnnual Review of Immunology, 1998
- Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cellsCurrent Biology, 1996
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature, 1995
- Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.Journal of Clinical Investigation, 1995