title: Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease.
abstract: Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased.
authors.affiliation: Department of Medicine, Palo Alto VA Medical Center, Stanford University School of Medicine Digestive Disease Center, Palo Alto, CA 94304, USA. dtoivola@stanford.edu
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
authors.forename: Nam-On
authors.initials: NO
authors.lastname: Ku
authors.forename: Evelyn Z
authors.initials: EZ
authors.lastname: Resurreccion
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wright
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
mesh_terms: D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D018450:Disease Progression; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D053538:Keratin-18; D053533:Keratin-8; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D015415:Biomarkers; C488421:KRT18 protein, human; C426203:KRT8 protein, human; D053538:Keratin-18; D053533:Keratin-8; C486595:Krt8 protein, mouse; D016753:Interleukin-10; D007633:Keratins