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


CONCLUSIONS
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.
Department of Physiology, School of Pharmacy, University of Valencia, Valencia, Spain.
Ana M
AM
Tormos
Alessandro
A
Arduini
Raquel
R
Talens-Visconti
Ivan
I
del Barco Barrantes
Angel R
AR
Nebreda
Juan
J
Sastre
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002908:Chronic Disease; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D048749:Cytokinesis; D004195:Disease Models, Animal; D018450:Disease Progression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate
D056744:Cyclin B1; D019938:Cyclin D1; D048308:Mitogen-Activated Protein Kinase 14; D048370:MAP Kinase Kinase 2