GSK-3βInhibition 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.

Xuebijing injection alleviates cytokine-induced inflammatory liver injury in CLP-induced septic rats through induction of suppressor of cytokine signaling 1

“…Evidence indicates that inflammatory cytokines play an important role in sepsis; pro-inflammatory cytokines and anti-inflammatory cytokines counteract each other and reach an immunological equilibrium, which leads to various types of tissue damage and organ injury (8). In the present study, elevated TNF-α, IL-6 and IL-10 levels were observed in the livers of rats in the CLP group in comparison with those in the control group, which is consistent with previous studies (27,28). Moreover, Xuebijing injection has been found to reduce the secretion of TNF-α and IL-6 by Kupffer cells in livers of rats with heart stroke (29), and promote IL-10 expression in rabbits with oleic acid-induced acute lung injury (30).…”

Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease

“…This kinase is an upstream activator Akt (PKB) and this in turn inhibits the GSK-3␤ activity via phosphorylation of ser9, allowing glycogen synthase to be dephosphorylated and glycogen synthesis to be started [28]. Inactivation of GSK-3␤ by the PI3K/Akt signaling pathway also participate in the regulation of inflammatory pathways, as it has been shown that Akt induced inhibition of GSK-3␤ negatively modulate the NF-B pathway [29]. Moreover, it has been demonstrated that GSK-3 inhibits production of pro-inflammatory cytokines (like IL-␤, IL-6 and IFN-␥) and increases release of antiinflammatory cytokines (like IL-10) [30].…”

SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia

“…A growing number of studies demonstrate a pathogenic role for GSK3␤ in end-organ damage in murine models of sepsis. Liver injury has been shown to be mediated by GSK3␤ activity and hepatocellular injury decreases with the use of GSK3␤ inhibitors (26,27). More recently, murine models of ARDS demonstrate an active role of GSK3␤ in mediating acute lung inflammation and alveolar damage (28,29).…”