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GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.

Zhang H, Wang W, Fang H, Yang Y, Li X, He J, Jiang X, Wang W, Liu S, Hu J, Liu A, Dahmen U, Dirsch O - Mediators Inflamm. (2014)

Bottom Line: The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.

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.

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GSK-3β inhibition improves survival and protects against CLP-induced liver injury. The septic mice were treated with SB216763 (25 mg/kg, i.p.) or vehicle (DMSO) at 1 h, 6 h, and 12 h after CLP. (a) Liver samples were harvested at 6 h after CLP and were subjected to western blotting analysis of phosphorylated (serine 9) GSK-3β and phosphorylated glycogen synthases (GS). (b) ALT and AST levels were analyzed as a measure of hepatocellular injury. Data are shown as mean ± SD. *P < 0.05, #P < 0.01 compared with vehicle-treated group. (c) The liver specimens were sampled at 20 h after CLP and stained with hematoxylin and eosin staining (original magnification ×400). Representative images from 6 mice/group were selected. (d) The Kaplan-Meier method was used to determine the difference of survival rate after CLP. P value was analyzed by log rank test. *P < 0.05 compared with vehicle-treated group.
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fig1: GSK-3β inhibition improves survival and protects against CLP-induced liver injury. The septic mice were treated with SB216763 (25 mg/kg, i.p.) or vehicle (DMSO) at 1 h, 6 h, and 12 h after CLP. (a) Liver samples were harvested at 6 h after CLP and were subjected to western blotting analysis of phosphorylated (serine 9) GSK-3β and phosphorylated glycogen synthases (GS). (b) ALT and AST levels were analyzed as a measure of hepatocellular injury. Data are shown as mean ± SD. *P < 0.05, #P < 0.01 compared with vehicle-treated group. (c) The liver specimens were sampled at 20 h after CLP and stained with hematoxylin and eosin staining (original magnification ×400). Representative images from 6 mice/group were selected. (d) The Kaplan-Meier method was used to determine the difference of survival rate after CLP. P value was analyzed by log rank test. *P < 0.05 compared with vehicle-treated group.

Mentions: To determine whether GSK-3β inhibition could attenuate liver injury during sepsis, GSK-3β inhibitor SB216763 was administrated to mice at 1 h, 6 h, and 12 h following CLP. As shown in Figure 1(a), compared with sham controls, the phosphorylated (serine 9) GSK-3β levels in the liver tissue were reduced at 6 h following CLP, suggesting GSK-3β was activated by the CLP insult. The inhibition of liver GSK-3β activity in vivo was indicated by the reduced phosphorylation of glycogen synthase, a downstream substrate of GSK-3β. As shown in Figure 1(b), compared with the vehicle-treated group, CLP resulted in significant increase in the serum levels of ALT and AST. However, SB216763 administration significantly attenuated the liver injury caused by CLP. The histologic examination showed significant liver tissue injury following CLP, as indicated by swollen hepatocytes and leukocyte infiltration. The inhibition of GSK-3β resulted in significant attenuation of these changes (Figure 1(c)). To address whether GSK-3β inhibition was of benefit for septic mice induced by CLP, survival was then assessed at 48 h following CLP. As shown in Figure 1(d), GSK-3β inhibitor SB216763 treatment significantly increased the survival rate of mice. Vehicle-treated mice had a 48 h survival of 27%. In contrast, the survival rate of mice treated with SB216763 was 53%.


GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.

Zhang H, Wang W, Fang H, Yang Y, Li X, He J, Jiang X, Wang W, Liu S, Hu J, Liu A, Dahmen U, Dirsch O - Mediators Inflamm. (2014)

GSK-3β inhibition improves survival and protects against CLP-induced liver injury. The septic mice were treated with SB216763 (25 mg/kg, i.p.) or vehicle (DMSO) at 1 h, 6 h, and 12 h after CLP. (a) Liver samples were harvested at 6 h after CLP and were subjected to western blotting analysis of phosphorylated (serine 9) GSK-3β and phosphorylated glycogen synthases (GS). (b) ALT and AST levels were analyzed as a measure of hepatocellular injury. Data are shown as mean ± SD. *P < 0.05, #P < 0.01 compared with vehicle-treated group. (c) The liver specimens were sampled at 20 h after CLP and stained with hematoxylin and eosin staining (original magnification ×400). Representative images from 6 mice/group were selected. (d) The Kaplan-Meier method was used to determine the difference of survival rate after CLP. P value was analyzed by log rank test. *P < 0.05 compared with vehicle-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4265684&req=5

fig1: GSK-3β inhibition improves survival and protects against CLP-induced liver injury. The septic mice were treated with SB216763 (25 mg/kg, i.p.) or vehicle (DMSO) at 1 h, 6 h, and 12 h after CLP. (a) Liver samples were harvested at 6 h after CLP and were subjected to western blotting analysis of phosphorylated (serine 9) GSK-3β and phosphorylated glycogen synthases (GS). (b) ALT and AST levels were analyzed as a measure of hepatocellular injury. Data are shown as mean ± SD. *P < 0.05, #P < 0.01 compared with vehicle-treated group. (c) The liver specimens were sampled at 20 h after CLP and stained with hematoxylin and eosin staining (original magnification ×400). Representative images from 6 mice/group were selected. (d) The Kaplan-Meier method was used to determine the difference of survival rate after CLP. P value was analyzed by log rank test. *P < 0.05 compared with vehicle-treated group.
Mentions: To determine whether GSK-3β inhibition could attenuate liver injury during sepsis, GSK-3β inhibitor SB216763 was administrated to mice at 1 h, 6 h, and 12 h following CLP. As shown in Figure 1(a), compared with sham controls, the phosphorylated (serine 9) GSK-3β levels in the liver tissue were reduced at 6 h following CLP, suggesting GSK-3β was activated by the CLP insult. The inhibition of liver GSK-3β activity in vivo was indicated by the reduced phosphorylation of glycogen synthase, a downstream substrate of GSK-3β. As shown in Figure 1(b), compared with the vehicle-treated group, CLP resulted in significant increase in the serum levels of ALT and AST. However, SB216763 administration significantly attenuated the liver injury caused by CLP. The histologic examination showed significant liver tissue injury following CLP, as indicated by swollen hepatocytes and leukocyte infiltration. The inhibition of GSK-3β resulted in significant attenuation of these changes (Figure 1(c)). To address whether GSK-3β inhibition was of benefit for septic mice induced by CLP, survival was then assessed at 48 h following CLP. As shown in Figure 1(d), GSK-3β inhibitor SB216763 treatment significantly increased the survival rate of mice. Vehicle-treated mice had a 48 h survival of 27%. In contrast, the survival rate of mice treated with SB216763 was 53%.

Bottom Line: The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan 430070, China.

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.

Show MeSH
Related in: MedlinePlus