title: Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells.
abstract: Mannan binding lectin (MBL)-associated serine protease type 1 (MASP-1) has a central role in the lectin pathway of complement activation and is required for the formation of C3 convertase. The activity of MASP-1 in the peripheral blood has been identified previously as a highly significant predictor of the severity of liver fibrosis in hepatitis C virus (HCV) infection, but not in liver disease of other aetiologies. In this study we tested the hypotheses that expression of MASP-1 may promote disease progression in HCV disease by direct activation of hepatic stellate cells (HSCs) and may additionally be up-regulated by HCV. In order to do so, we utilized a model for the maintenance of primary human HSC in the quiescent state by culture on basement membrane substrate prior to stimulation. In comparison to controls, recombinant MASP-1 stimulated quiescent human HSCs to differentiate to the activated state as assessed by both morphology and up-regulation of HSC activation markers α-smooth muscle actin and tissue inhibitor of metalloproteinase 1. Further, the expression of MASP-1 was up-regulated significantly by HCV infection in hepatocyte cell lines. These observations suggest a new role for MASP-1 and provide a possible mechanistic link between high levels of MASP-1 and the severity of disease in HCV infection. Taken together with previous clinical observations, our new findings suggest that the balance of MASP-1 activity may be proinflammatory and act to accelerate fibrosis progression in HCV liver disease.
authors.affiliation: School of Molecular Medical Sciences, University of Nottingham, Leicester, UK; School of Pharmacy, University of Nottingham, Leicester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Saeed
authors.forename: K
authors.initials: K
authors.lastname: Baloch
authors.forename: R J P
authors.initials: RJ
authors.lastname: Brown
authors.forename: R
authors.initials: R
authors.lastname: Wallis
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Dexter
authors.forename: C P
authors.initials: CP
authors.lastname: McClure
authors.forename: K
authors.initials: K
authors.lastname: Shakesheff
authors.forename: B J
authors.initials: BJ
authors.lastname: Thomson
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D037582:Complement Pathway, Mannose-Binding Lectin / Q000276:immunology; D018450:Disease Progression; D016174:Hepacivirus / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000276:immunology*; D006526:Hepatitis C / Q000150:complications / Q000276:immunology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology*; D037601:Mannose-Binding Lectin / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D037601:Mannose-Binding Lectin; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; C084067:MASP1 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases
keywords: MASP-1; fibrosis; hepatitis C; innate immune response