Hepatocyte cytokeratins are hyperphosphorylated at multiple sites in humanalcoholic hepatitis and in a Mallory body mouse model

Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) a ccumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). S tudies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation, However, no data ex ist on phosphorylation of CK8/18 in human AR. In this study, antibodies tha t selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, h uman AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine ( DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocy te cytokeratins become hyperphosphorylated at multiple sites in AH and in D DC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytosk eleton, In long-term DDC-intoxicated mice as well as in human AH, MBs prefe rentially contain hyperphosphorylated CK8/18 as compared with the cytoplasm ic cytokeratin intermediate filament network suggesting that CK8/18 hyperph osphorylation 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 p rotein kinases known to be activated in stress responses,mitosis, and apopt osis.