Glycogen synthase kinase-3beta suppresses tumor necrosis factor-alpha expression in cardiomyocytes during lipopolysaccharide stimulation.
This study was to investigate the role of glycogen synthase kinase-3beta (GSK-3beta) in cardiomyocyte tumor necrosis factor-alpha (TNF-alpha) expression induced by lipopolysaccharide (LPS). In cultured neonatal mouse cardiomyocytes, LPS induced TNF-alpha expression and increased GSK-3beta activation. Inhibition of GSK-3beta by SB216763 or by over-expression of a dominant negative mutant of GSK-3beta significantly enhanced TNF-alpha expression in LPS-stimulated cardiomyocytes, in association with an increase in p65 phosphorylation. In contrast, over-expression of GSK-3beta by adenoviral vectors containing wild-type GSK-3beta or a constitutively active GSK-3beta attenuated TNF-alpha expression induced by LPS. Further evidence to support the inhibitory role of GSK-3beta in TNF-alpha expression is that protein kinase B (Akt) signaling, an upstream inhibitor of GSK-3beta, promotes TNF-alpha expression in LPS-stimulated cardiomyocytes and this action of Akt signaling can be mimicked by GSK-3beta inactivation. Our study demonstrates that GSK-3beta plays an inhibitory role in cardiomyocyte TNF-alpha expression during LPS stimulation, and it may be a potential therapeutic target for sepsis.
Shen
E
E
Center for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada.
Fan
Jue
J
Peng
Tianqing
T
D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3