Glycogen synthase kinase 3beta and beta-catenin pathway is involved in toll-like receptor 4-mediated NADPH oxidase 1 expression in macrophages.
Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood. We found that LPS causes beta-catenin accumulation by glycogen synthase kinase 3beta (GSK3beta) inactivation, and that beta-catenin accumulation increases Nox1 expression. LPS induced Nox1 mRNA expression and reactive oxygen species generation in Raw264.7 cells. Using bone marrow-derived macrophages from toll-like receptor 4 mutant mice, we also tested whether LPS-induced Nox1 expression is toll-like receptor 4 dependent. LPS caused GSK3beta phosphorylation, induced beta-catenin accumulation and increased nuclear translocation. The GSK3beta inhibitor LiCl potentiated LPS-induced Nox1 expression in accordance with beta-catenin accumulation and nuclear translocation. Conversely, ectopic expression of a constitutively active GSK3beta mutant severely attenuated Nox1 expression. These findings identify a novel regulatory pathway controlling Nox1 expression by LPS-stimulated macrophages.
Kim
Jin-Sik
JS
Department of Biochemistry & Molecular Biology, Yeungnam University, Daegu, Korea.
Yeo
Seungeun
S
Shin
Dong-Gu
DG
Bae
Yoe-Sik
YS
Lee
Jae-Jin
JJ
Chin
Byung-Rho
BR
Lee
Chu-Hee
CH
Baek
Suk-Hwan
SH
D000818:Animals; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008070:Lipopolysaccharides / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D000074624:NADPH Oxidase 1; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051176:beta Catenin; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride