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.
Department of Biochemistry & Molecular Biology, Yeungnam University, Daegu, Korea.
Jin-Sik
JS
Kim
Seungeun
S
Yeo
Dong-Gu
DG
Shin
Yoe-Sik
YS
Bae
Jae-Jin
JJ
Lee
Byung-Rho
BR
Chin
Chu-Hee
CH
Lee
Suk-Hwan
SH
Baek
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