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(American Journal of Pathology. 2000;156:1263-1274.)
© 2000 American Society for Investigative Pathology

Regular Articles

Cytokeratin 8 Protects from Hepatotoxicity, and Its Ratio to Cytokeratin 18 Determines the Ability of Hepatocytes to Form Mallory Bodies

Kurt Zatloukal^*, Cornelia Stumptner^*, Manfred Lehner^*, Helmut Denk^*, Helene Baribault, Leonid G. Eshkind and Werner W. Franke

From the Department of Pathology,^*
University of Graz, Graz, Austria; The Burnham Institute,
La Jolla, California; and the Division of Cell Biology,
German Cancer Research Center, Heidelberg, Germany

In alcoholic hepatitis, a severe form of alcohol-induced toxic liver injury, as well as in experimental intoxication of mice with the porphyrinogenic drugs griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, hepatocytes form cytoplasmic protein aggregates (Mallory bodies; MBs) containing cytokeratins (CKs) and non-CK components. Here we report that mice lacking the CK8 gene and hence CK intermediate filaments in hepatocytes, but still expressing the type I partner, ie, the CK18 gene, do not form MBs but suffer from extensive porphyria and progressive toxic liver damage, leading to the death of a considerable number of animals (7 of 12 during 12 weeks of intoxication). Our observations show that 1) in the absence of CK8 as well as in the situation of a relative excess of CK18 over CK8 no MBs are formed; 2) the loss of CK8 is not compensated by other type II CKs; and 3) porphyria and toxic liver damage are drastically enhanced in the absence of CK8. Our results point to a protective role of CKs in certain types of toxic liver injury and suggest that MBs by themselves are not harmful to hepatocytes but may be considered as a product of a novel defense mechanism in hepatocytes.

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