title: Hepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2.
abstract: Hepatic stellate cells (HSCs) represent the main fibrogenic cell type accumulating extracellular matrix in the liver. Recent data suggest that hepatitis C virus (HCV) core protein may directly activate HSCs. Therefore, we examined the influence of recombinant HCV core protein on human HSCs. Primary human HSCs and the human HSC line LX-2 were stimulated with recombinant HCV proteins core and envelope 2 protein. Expression of procollagen type I α-1, α-smooth muscle actin, cysteine- and glycine-rich protein 2, glial fibrillary acidic protein, tissue growth factor β1, matrix metalloproteinases 2 (MMP2) and 13, tissue inhibitor of metalloproteinases 1 and 2 was investigated by real-time PCR. Intracellular signaling pathways of ERK1/2, p38 and, jun-amino-terminal kinase (JNK) were analyzed by western blot analysis. Recombinant HCV core protein induced upregulation of procollagen type I α-1, α-smooth muscle actin, MMP 2 and 13, tissue inhibitor of metalloproteinases 1 and 2, tissue growth factor β1, cysteine- and glycine-rich protein 2, and glial fibrillary acidic protein mRNA expression, whereas HCV envelope 2 protein did not exert any significant effect. Blocking of toll-like receptor 2 (TLR2) with a neutralizing antibody prevented mRNA upregulation by HCV core protein confirming that the TLR2 pathway was involved. Furthermore, western blot analysis revealed HCV-induced phosphorylation of the TLR2-dependent signaling molecules ERK1/2, p38 and JNK mitogen-activated kinases. Our in vitro results demonstrate a direct effect of HCV core protein on activation of HSCs toward a profibrogenic state, which is mediated via the TLR2 pathway. Manipulating the TLR2 pathway may thus provide a new approach for antifibrotic therapies in HCV infection.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Coenen
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Bettina
authors.initials: B
authors.lastname: Langhans
authors.forename: Andreas
authors.initials: A
authors.lastname: Glässner
authors.forename: Daniela
authors.initials: D
authors.lastname: Schulte
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers; D006526:Hepatitis C / Q000503:physiopathology*; D006801:Humans; D008099:Liver / Q000473:pathology*; D016133:Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014758:Viral Core Proteins / Q000502:physiology*
chemical_list: D017931:DNA Primers; D051195:Toll-Like Receptor 2; D014758:Viral Core Proteins