“
“p38α mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor β, tumor necrosis factor-α, interleukin-1β, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38α-deficient cells. Our aim was to assess the role of p38α 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 p38α knockout selleck mice by bile duct ligation and animals were sacrificed at 12 and 28 days. p38α knockout mice exhibited a 50% decrease in mean life-span after cholestasis induction. MK0683 MK2 phosphorylation was markedly reduced in liver of p38α-deficient mice upon chronic cholestasis. Hepatocyte

growth was reduced and hepatomegaly was absent in p38α-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 p38α-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 p38α-deficient mice. p38α-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 p38α-deficient mice. Conclusion: Our results highlight a key role of p38α in hepatocyte proliferation, in the development of hepatomegaly, and in survival during chronic inflammation such as biliary cirrhosis. (HEPATOLOGY 2013) Mitogen-activated protein kinases (MAPKs) are essential for the cellular response against injury and for regulation of cell death and tissue homeostasis. p38 MAPKs are a family of serine/threonine

protein kinases activated by environmental and genotoxic stress that have key roles in the Aspartate control of cell proliferation, differentiation, and survival, as well as in the regulation of the inflammatory response.1 p38α is the most abundant kinase within the p38 MAPK family and displays relevant biological roles in pathophysiology. Increased proliferation and impaired differentiation have been considered hallmarks of p38α-deficient cells.2 Mice with liver-specific deletion of p38α exhibited enhanced hepatocyte proliferation after partial hepatectomy2 and developed more liver tumors with increased numbers of proliferative tumor cells.3 p38α may repress cell proliferation by antagonizing the c-Jun N-terminal kinase (JNK)/c-Jun pathway.