title: Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis.
abstract: OBJECTIVE
  Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis.
  
  
  METHODS
  Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry.
  
  
  RESULTS
  All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs.
  
  
  CONCLUSIONS
  Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. kenichih@med.kanazawa-u.ac.jp
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Mayumi
authors.initials: M
authors.lastname: Chiba
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okamura
authors.forename: Maylee
authors.initials: M
authors.lastname: Hsu
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Saya
authors.initials: S
authors.lastname: Igarashi
authors.forename: Xiang Shan
authors.initials: XS
authors.lastname: Ren
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Hajime
authors.initials: H
authors.lastname: Ohta
authors.forename: Satomi
authors.initials: S
authors.lastname: Kasashima
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kawashima
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D001647:Bile Acids and Salts; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D051193:Toll-Like Receptors