title: GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.
abstract: Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.
authors.affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan 430070, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Anhui Medical University, Hefei 230032, China.
authors.forename: Haoshu
authors.initials: H
authors.lastname: Fang
authors.affiliation: Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan 430070, China.
authors.forename: Junli
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan 430070, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China.
authors.forename: Shenpei
authors.initials: S
authors.lastname: Liu
authors.affiliation: Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China.
authors.forename: Jifa
authors.initials: J
authors.lastname: Hu
authors.affiliation: Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China ; Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital of Jena, Friedrich-Schiller-University Jena, 07747 Jena, Germany.
authors.forename: Anding
authors.initials: A
authors.lastname: Liu
authors.affiliation: Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital of Jena, Friedrich-Schiller-University Jena, 07747 Jena, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Dahmen
authors.affiliation: Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital of Jena, Friedrich-Schiller-University Jena, 07747 Jena, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Dirsch
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007211:Indoles; D015850:Interleukin-6; D008301:Maleimides; D016328:NF-kappa B; C417521:SB 216763; C577686:interleukin-6, mouse; D009195:Peroxidase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3