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(American Journal of Pathology. 2000;156:77-90.)
© 2000 American Society for Investigative Pathology

Regular Articles

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Conny Stumptner^*, M. Bishr Omary, Peter Fickert, Helmut Denk^* and Kurt Zatloukal^*

From the Departments of Pathology^*
and Medicine,
University of Graz, Graz, Austria; and the Department of Medicine,
Palo Alto VA Medical Center and Stanford University, Palo Alto, California

Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.

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