AKT regulates IL-1β-induced proliferation and activation of hepatic stellate cells

Background:Activated hepatic stellate cells(HSCs)are closely involved in the initiation,perpetuation,and resolution of liver fibrosis.Pro-inflammatory cytokine levels are positively correlated with the transition from liver injury to fibrogenesis and contribute to HSC pathophysiology in liver fibrosis.Methods:In this study,we investigated the effect of the pro-inflammatory cytokine interleukin(IL)-1βon the proliferation and signaling pathways involved in fibrogenesis in LX-2 cells,an HSC cell line,using western blotting and cell proliferation assays.Results:IL-1βincreased the proliferation rate andα-smooth muscle actin(SMA)expression of LX-2 cells in a dose-dependent manner.Within 1 h after IL-1βtreatment,c-Jun N-terminal kinase(JNK),p38,and nuclear factor-κB(NF-κB)signaling was activated in LX-2 cells.Subsequently,protein kinase B(AKT)phosphorylation and an increase inα-SMA expression were observed in LX-2 cells.Each inhibitor of JNK,p38,or NF-κB decreased cell proliferation,AKT phosphorylation,andα-SMA expression in IL-1β-treated LX-2 cells.Conclusion:These results indicate that JNK,p38,and NF-κB signals converge at AKT phosphorylation,leading to LX-2 activation by IL-1β.Therefore,the AKT signaling pathway can be used as a target for alleviating liver fibrosis by the inflammatory cytokine IL-1β.

Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives

Cirrhosis occurs as a result of various chronic liver injuries,which may be caused by viral infections,alcohol abuse and the administration of drugs and chemicals. Recently,bone marrow cells(BMCs),hematopoietic stem cells(HSCs) and mesenchymal stem cells(MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs,HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC,HSC and MSC treatments are still not fully characterized,the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses,reduce hepatocyte apoptosis,increase hepatocyte regeneration,reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs,HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs,HSCs and MSCs for the improvement of liver function.