hepatocyte ikk2 protects mdr2？？ mice from chronic liver failure小鼠肝细胞ikk2保护mdr2 从慢性肝衰竭.pdfVIP

Hepatocyte IKK2 Protects Mdr22/ 2 Mice from Chronic Liver Failure 1 1 1¤a 1¤b 2 Hanno Ehlken , Vangelis Kondylis , Jan Heinrichsdorff , Laura Ochoa-Callejero , Tania Roskams , Manolis Pasparakis1* 1 Institute for Genetics, Centre for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany, 2 Department of Pathology, Catholic University of Leuven, Leuven, Belgium Abstract Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr22/ 2) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-kB by expression of an IkBa super-repressor (IkBaSR) transgene in hepatocytes was shown to prevent HCC development in Mdr22/ 2 mice, suggesting that NF-kB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-kB 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-kB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr22/ 2 mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr22/ 2 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