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Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis
  1. Kenichi Harada1,
  2. Mayumi Chiba1,
  3. Atsushi Okamura1,
  4. Maylee Hsu1,
  5. Yasunori Sato1,
  6. Saya Igarashi1,
  7. Xiang Shan Ren1,
  8. Hiroko Ikeda2,
  9. Hajime Ohta3,
  10. Satomi Kasashima4,
  11. Atsuhiro Kawashima4,
  12. Yasuni Nakanuma1
  1. 1Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
  2. 2Division of Pathology, Kanazawa University Hospital, Kanazawa, Japan
  3. 3Department of Gastroenterology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
  4. 4Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
  1. Correspondence to Dr Kenichi Harada, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan; kenichih{at}


Aims 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.

  • Hepatic stellate cell
  • hepatic fibrosis
  • biliary epithelial cells
  • Toll-like receptor
  • MCP-1
  • biliary innate immunity
  • colorectal cancer
  • gall bladder
  • oncogenes
  • p53
  • pancreas
  • biliary
  • liver
  • liver disease
  • liver cancer
  • histopathology

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  • Funding This work was supported by Grants-in-aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan and Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the Kanazawa University Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.