Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.
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.
Martin
Michael
M
Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2170, USA. michmart@uab.edu
Rehani
Kunal
K
Jope
Richard S
RS
Michalek
Suzanne M
SM
D000818:Animals; D050882:CREB-Binding Protein; D002474:Cell-Free System; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012772:Shock, Septic / Q000517:prevention & control; D013997:Time Factors; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004268:DNA-Binding Proteins; D004731:Endotoxins; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C417521:SB 216763; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015534:Trans-Activators; D016753:Interleukin-10; D018664:Interleukin-12; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D038362:Glycogen Synthase Kinase 3