Liver-specific p38[alpha] deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice

p38[alpha] mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor [beta], tumor necrosis factor-[alpha], interleukin-1[beta], and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38[alpha]-deficient cells. Our aim was to assess the role of p38[alpha] in the progression of biliary cirrhosis induced by chronic cholestasis as an experimental model of chronic inflammation associated with hepatocyte proliferation, apoptosis, oxidative stress, and fibrogenesis. Cholestasis was induced in wildtype and liver-specific p38[alpha] knockout mice by bile duct ligation and animals were sacrificed at 12 and 28 days. p38[alpha] knockout mice exhibited a 50% decrease in mean life-span after cholestasis induction. MK2 phosphorylation was markedly reduced in liver of p38[alpha]-deficient mice upon chronic cholestasis. Hepatocyte growth was reduced and hepatomegaly was absent in p38[alpha]-deficient mice during chronic cholestasis through down-regulation of both AKT and mammalian target of rapamycin. Cyclin D1 and cyclin B1 were up-regulated in liver of p38[alpha]-deficient mice upon chronic cholestasis, but unexpectedly proliferating cell nuclear antigen was down-regulated at 12 days after cholestasis induction and the mitotic index was very high upon cholestasis in p38[alpha]-deficient mice. p38[alpha]-knockout hepatocytes exhibited cytokinesis failure evidenced by an enhanced binucleation rate. As chronic cholestasis evolved the binucleation rate decreased in wildtype animals, whereas it remained high in p38[alpha]-deficient mice. Conclusion: Our results highlight a key role of p38[alpha] in hepatocyte proliferation, in the development of hepatomegaly, and in survival during chronic inflammation such as biliary cirrhosis. (HEPATOLOGY 2013) [PUBLICATION ABSTRACT]