title: Role of TLR4-Mediated PI3K/AKT/GSK-3β Signaling Pathway in Apoptosis of Rat Hepatocytes.
abstract: We investigated the mechanism of the Toll-like receptor 4- (TLR4-) mediated PI3K/AKT/GSK-3β signaling pathway in rat hepatocytes apoptosis induced by LPS. The cultured rat hepatocytes were treated with LPS alone or first pretreated with TLR4 inhibitor, AKT inhibitor, and GSK-3β inhibitor, respectively, and then stimulated with the same dose of LPS. Cell viability, cell apoptotic rate, and apoptosis morphology were assessed; the level of P-AKT(Ser473), P-GSK-3β(Ser9), and active Caspase-3 and the ratio of Bax/Bcl-2 were evaluated. The results indicated that cell viability decreased, while cell apoptotic rate increased with time after LPS stimulation. The expression of P-AKT(Ser473) and P-GSK-3β(Ser9) in the LPS group decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased. These effects were attenuated by pretreatment with CLI-095. In addition, the apoptotic ratio decreased after pretreatment with LiCl but increased following pretreatment with LY294002. The expression of P-AKT(Ser473) further decreased following pretreatment with LY294002 and the expression of P-GSK-3β(Ser9) increased following pretreatment with LiCl. Moreover, pretreatment with CLI-095 weakened LPS-induced nuclear translocation of GSK-3β. Our findings suggest that the TLR4-mediated PI3K/AKT/GSK-3β signaling pathway is present in rat hepatocytes and participates in apoptosis of BRL-3A cells.
authors.affiliation: Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Department of Infectious Disease, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Daorong
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Science Technology and Industry, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pathophysiology, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Gan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3