Hepatocyte IKK2 protects Mdr2-/- mice from chronic liver failure

TY - JOUR

T1 - Hepatocyte IKK2 protects Mdr2-/- mice from chronic liver failure

AU - Ehlken, Hanno

AU - Kondylis, Vangelis

AU - Heinrichsdorff, Jan

AU - Ochoa-Callejero, Laura

AU - Roskams, Tania

AU - Pasparakis, Manolis

PY - 2011/1/1

Y1 - 2011/1/1

N2 - UNLABELLED: Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/-)) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR) transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/-) mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/-) mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/-) mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-)IKK2(Hep-KO) mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs.CONCLUSION: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.

AB - UNLABELLED: Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/-)) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR) transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/-) mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/-) mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/-) mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-)IKK2(Hep-KO) mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs.CONCLUSION: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.

KW - Animals

KW - Bile Acids and Salts

KW - Cell Death

KW - Cell Proliferation

KW - Cells, Cultured

KW - Cytoprotection

KW - End Stage Liver Disease

KW - Hepatocytes

KW - I-kappa B Kinase

KW - Jaundice

KW - Liver

KW - Liver Cirrhosis

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - P-Glycoproteins

KW - Wasting Syndrome

U2 - 10.1371/journal.pone.0025942

DO - 10.1371/journal.pone.0025942

M3 - SCORING: Journal article

C2 - 22022477

VL - 6

SP - e25942

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 10

ER -