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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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Related in: MedlinePlus

GSK-3β inhibition attenuates the inflammatory cytokine production following CLP. (a) GSK-3β inhibition altered mRNA expression of TNF-α, IL-6, IL-1β, and IL-10 in the liver of septic mice. (b) Serum TNF-α and IL-6 levels were assessed by ELISA. Data are shown as mean ± SD. n = 6 per group. *P < 0.05, #P < 0.01 compared with vehicle-treated group.
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fig2: GSK-3β inhibition attenuates the inflammatory cytokine production following CLP. (a) GSK-3β inhibition altered mRNA expression of TNF-α, IL-6, IL-1β, and IL-10 in the liver of septic mice. (b) Serum TNF-α and IL-6 levels were assessed by ELISA. Data are shown as mean ± SD. n = 6 per group. *P < 0.05, #P < 0.01 compared with vehicle-treated group.

Mentions: To test whether GSK-3β inhibition could attenuate liver injury during sepsis via inhibition of inflammation, the production of TNF-α, IL-6, IL-1β, and IL-10 was analyzed at 6 h following CLP. As shown in Figure 2(a), CLP resulted in significant increase in the mRNA levels of TNF-α, IL-6, IL-1β, and IL-10. Liver TNF-α, IL-6, and IL-1β mRNA levels were significantly attenuated by the administration of SB216763. In contrast, the IL-10 mRNA levels were significantly increased by the SB216763 administration. Furthermore, the inhibition of GSK-3β significantly reduced the CLP-induced production of serum TNF-α and IL-6 levels (Figure 2(b)). The numbers of MPO staining positive neutrophils that infiltrated the liver were determined. Hepatic neutrophil infiltration was significantly increased at 20 h following CLP. However, SB216763 administration significantly reduced the CLP-induced increase in the infiltration of neutrophils (Figure 3). These results indicated that inhibition of GSK-3β relieved the inflammation in the liver following CLP.


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 attenuates the inflammatory cytokine production following CLP. (a) GSK-3β inhibition altered mRNA expression of TNF-α, IL-6, IL-1β, and IL-10 in the liver of septic mice. (b) Serum TNF-α and IL-6 levels were assessed by ELISA. Data are shown as mean ± SD. n = 6 per group. *P < 0.05, #P < 0.01 compared with vehicle-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4265684&req=5

fig2: GSK-3β inhibition attenuates the inflammatory cytokine production following CLP. (a) GSK-3β inhibition altered mRNA expression of TNF-α, IL-6, IL-1β, and IL-10 in the liver of septic mice. (b) Serum TNF-α and IL-6 levels were assessed by ELISA. Data are shown as mean ± SD. n = 6 per group. *P < 0.05, #P < 0.01 compared with vehicle-treated group.
Mentions: To test whether GSK-3β inhibition could attenuate liver injury during sepsis via inhibition of inflammation, the production of TNF-α, IL-6, IL-1β, and IL-10 was analyzed at 6 h following CLP. As shown in Figure 2(a), CLP resulted in significant increase in the mRNA levels of TNF-α, IL-6, IL-1β, and IL-10. Liver TNF-α, IL-6, and IL-1β mRNA levels were significantly attenuated by the administration of SB216763. In contrast, the IL-10 mRNA levels were significantly increased by the SB216763 administration. Furthermore, the inhibition of GSK-3β significantly reduced the CLP-induced production of serum TNF-α and IL-6 levels (Figure 2(b)). The numbers of MPO staining positive neutrophils that infiltrated the liver were determined. Hepatic neutrophil infiltration was significantly increased at 20 h following CLP. However, SB216763 administration significantly reduced the CLP-induced increase in the infiltration of neutrophils (Figure 3). These results indicated that inhibition of GSK-3β relieved the inflammation in the liver following CLP.

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