Liver-specific p38α deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice

Abstract

p38a mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor b, tumor necrosis factor-a, interleukin-1b, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38a-deficient cells. Our aim was to assess the role of p38a 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 p38a knockout mice by bile duct ligation and animals were sacrificed at 12 and 28 days. p38a knockout mice exhibited a 50% decrease in mean life-span after cholestasis induction. MK2 phosphorylation was markedly reduced in liver of p38a-deficient mice upon chronic cholestasis. Hepatocyte growth was reduced and hepatomegaly was absent in p38a-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 p38a-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 p38a-deficient mice. p38a-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 p38a-deficient mice. Conclusion: Our results highlight a key role of p38a in hepatocyte proliferation, in the development of hepatomegaly, and in survival during chronic inflammation such as biliary cirrhosis. (HEPATOLOGY 2013;57:1950-1961

RETRACTED ARTICLE: p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death

“…It was found that the effects of H 2 O 2 on L02 cell viability were dependent on its concentration (Figure 2A Because p38α has been implicated in the growth of liver cells 23,24 , we wondered whether miR-200a-3p affects liver cell proliferation by targeting p38α. As expected, similar results to those obtained with miR-200a-3p overexpression were obtained in cells with MAPK14 knockdown ( Figure 2E).…”

“…A recent study reported that hepatocyte growth was reduced in p38α-knockout mice during chronic cholestasis through the down-regulation of Akt phosphorylation levels 23 . As an important substrate of p38α, MAPKAPK2 mediates the HSP27-dependent activation of Akt by phosphorylating Akt at Ser473 38 .…”

“…As expected, similar results to those obtained with miR-200a-3p overexpression were obtained in cells with MAPK14 knockdown ( Figure 2E). It has been reported that hepatocyte growth could be inhibited in p38α-knock out mice during chronic cholestasis by down-regulating the levels of phosphorylated Akt 23 . In agreement with these findings, we showed that the levels of Akt phosphorylation on serine 473 were markedly reduced upon p38α knockdown or miR-200a-3p overexpression, whereas phosphorylation on threonine 308 remained unaffected ( Figure 2F).…”

Oxidative Mechanisms in Liver Senescence and Regeneration

“…For example, studies on palmitic acid-stimulated cells from a normal human hepatocyte cell line indicated that the mitogenic effect (1) was dependent on ROS production, in that it was inhibited by either N -acetylcysteine or catalase; (2) it was associated with increased expression and nuclear translocation of Nrf2; (3) the specifi c inhibition of p38-MAPK blocked the G1-S transition in these cells [ 183 ]. In line with the above results, a recent report indicates that p38-MAPK-knockout mice have reduced levels of hepatocyte proliferation and reduced regeneration after injury [ 176 ].…”

Extracellular-signal regulated kinase (Erk1/2), mitogen-activated protein kinase-activated protein kinase 2 (MK2) and tristetraprolin (TTP) comprehensively regulate injury-induced immediate early gene (IEG) response in in vitro liver organ culture

“…The authors suggest that the inactivation of p38MAPK is required for activation of Erk1/2. In addition, Tormos et al [4] showed that depletion of p38MAPKalpha caused a hepatocyte proliferation defect in which the depletion of p38MAPK in hepatocytes reduced cell growth by attenuation in the M phase during cell cycle. Thus, the molecular role of stress-induced kinases, p38MAPK, and one of its major substrates, MK2, in hepatocyte proliferation after injury is still enigmatic.…”