C. Stumptner et al., Hepatocyte cytokeratins are hyperphosphorylated at multiple sites in humanalcoholic hepatitis and in a Mallory body mouse model, AM J PATH, 156(1), 2000, pp. 77-90
Citations number
64
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
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.