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Augmented expression of hepatocytes growth factor activator inhibitor type 1 (HAI-1) in intrahepatic small bile ducts in primary biliary cirrhosis

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Abstract

The repair system of damaged biliary mucosa was not fully clarified so far in primary biliary cirrhosis (PBC). Given that related factors of the hepatocyte growth factor (HGF) such as HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1) participate in the repair of injured gastrointestinal mucosa, we investigated the involvement of the HGF/HGFA/HAI-1 system in PBC and control livers. The expression of HGFA, HAI-1, and c-Met was examined in PBC livers (n=24), diseased livers (control, n=30), and normal livers (n=15) by immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction. We examined the expression of HGFA, HAI-1, and c-Met, and the effect of HGF administration on cell proliferation and wound healing, and HAI expression in cultured mouse biliary epithelial cells (BECs). HAI-1 expression was faint in control livers, whereas it was significantly augmented in damaged small bile ducts, bile ductules, and periportal hepatocytes in PBC (p<0.05). HGFA and c-Met were homogeneously expressed in BECs in PBC and control livers. HAI-1 expression was increased at the front of wound healing and the treatment with HGF-enhanced HAI-1 expression, cell proliferation, and wound healing in cultured BECs. HGF/HGFA/HAI-1 system may participate in biliary mucosal repair as reported in gastrointestinal mucosal repair.

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References

  1. Auth MK, Joplin RE, Okamoto M, Ishida Y, McMaster P, Neuberger JM, Blaheta RA, Voit T, Strain AJ (2001) Morphogenesis of primary human biliary epithelial cells: induction in high-density culture or by coculture with autologous human hepatocytes. Hepatology 33:519–529

    Article  PubMed  CAS  Google Scholar 

  2. Desmet V, Gerber M, Hoofnagle J, Manns M, Scheuer P (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19(6):1513–1520

    PubMed  CAS  Google Scholar 

  3. Fussey S, Guest J, James O, Bassendine M, Yeaman S (1988) Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci U S A 85:8654–8658

    Article  PubMed  CAS  Google Scholar 

  4. Gershwin ME, Mackay IR, Sturgess A, Coppel RL (1987) Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138:3525–3531

    PubMed  CAS  Google Scholar 

  5. Halaban R, Rubin JS, Funasaka Y, Cobb M, Boulton T, Faletto D, Rosen E, Chan A, Yoko K, White W et al (1992) Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 7:2195–2206

    PubMed  CAS  Google Scholar 

  6. Itoh H, Kataoka H (2002) Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa. J Gastroenterol 37(Suppl 14):15–21

    PubMed  Google Scholar 

  7. Joplin R, Hishida T, Tsubouchi H, Daikuhara Y, Ayres R, Neuberger JM, Strain AJ (1992) Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor. J Clin Invest 90:1284–1289

    PubMed  CAS  Google Scholar 

  8. Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, Tsuneyama K, Nakamura M, Ishibashi H, Nakanuma Y, Gershwin ME, Harada M (2003) Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis. Gastroenterology 125:1379–1387

    Article  PubMed  Google Scholar 

  9. Kaplan M (1996) Primary biliary cirrhosis. New Engl J Med 335:1570–1580

    Article  PubMed  CAS  Google Scholar 

  10. Kataoka H, Suganuma T, Shimomura T, Itoh H, Kitamura N, Nabeshima K, Koono M (1999) Distribution of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in human tissues. Cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues. J Histochem Cytochem 47:673–682

    PubMed  CAS  Google Scholar 

  11. Kataoka H, Itoh H, Hamasuna R, Meng JY, Koono M (2001) Pericellular activation of hepatocyte growth factor/scatter factor (HGF/SF) in colorectal carcinomas: roles of HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1). Hum Cell 14:83–93

    PubMed  CAS  Google Scholar 

  12. Katayanagi K, Kono N, Nakanuma Y (1998) Isolation, culture and characterization of biliary epithelial cells from different anatomical levels of the intrahepatic and extrahepatic biliary tree from a mouse. Liver 18:90–98

    PubMed  CAS  Google Scholar 

  13. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL, Kaplan MM, Gershwin ME (2002) Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest 109:1231–1240

    Article  PubMed  CAS  Google Scholar 

  14. Nakanuma Y, Ohta G (1979) Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis. Gastroenterology 76:1326–1332

    PubMed  CAS  Google Scholar 

  15. Nakanuma Y, Sasaki M (1989) Expression of blood-group-related antigens in the intrahepatic biliary tree and hepatocytes in normal livers and various hepatobiliary diseases. Hepatology 10:174–178

    Article  PubMed  CAS  Google Scholar 

  16. Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, Haber J, Katz G, Lindor K (2002). Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol 17:196–202

    Article  PubMed  CAS  Google Scholar 

  17. Nozaki I, Lunz JG 3rd, Specht S, Park JI, Giraud AS, Murase N, Demetris AJ (2004) Regulation and function of trefoil factor family 3 expression in the biliary tree. Am J Pathol 165:1907–1920

    PubMed  CAS  Google Scholar 

  18. Portmann B, Nakanuma Y (2001) Diseases of the bile ducts. In: MacSween R, Burt A, Portmann BC, Ishak K, Scheuer P, Anthony P (eds) Pathology of the liver. Churchill Livingstone, London, pp 435–506

    Google Scholar 

  19. Sasaki M, Tsuneyama K, Nakanuma Y (2003) Aberrant expression of trefoil factor family 1 in biliary epithelium in hepatolithiasis and cholangiocarcinoma. Lab Invest 83:1403–1413

    Article  PubMed  CAS  Google Scholar 

  20. Sasaki M, Tsuneyama K, Saito T, Kataoka H, Mollenhauer J, Poustka A, Nakanuma Y (2004) Site-characteristic expression and induction of trefoil factor family 1, 2 and 3 and malignant brain tumor-1 in normal and diseased intrahepatic bile ducts relates to biliary pathophysiology. Liver Int 24:29–37

    Article  PubMed  CAS  Google Scholar 

  21. Sasaki M, Ikeda H, Haga H, Manabe T, Nakanuma Y (2005) Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. J Pathol 205:451–459

    Article  PubMed  Google Scholar 

  22. Scheuer P (1994) Liver biopsy interpretation, 5th edn. Saunders, London

    Google Scholar 

  23. Sherlock S, Dooley J (1993) Primary biliary cirrhosis. In: Diseases of the liver and biliary system. Blackwell, London, pp 236

    Google Scholar 

  24. Shimoda S, Van de Water J, Ansari A, Nakamura M, Ishibashi H, Coppel RL, Lake J, Keeffe EB, Roche TE, Gershwin ME (1998) Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest 102:1831–1840

    Article  PubMed  CAS  Google Scholar 

  25. Shiota G, Okano J, Kawasaki H, Kawamoto T, Nakamura T (1995) Serum hepatocyte growth factor levels in liver diseases: clinical implications. Hepatology 21:106–112

    Article  PubMed  CAS  Google Scholar 

  26. Shiota G, Rhoads DB, Wang TC, Nakamura T, Schmidt EV (1992) Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells. Proc Natl Acad Sci U S A 89:373–377

    Article  PubMed  CAS  Google Scholar 

  27. Strain AJ, Wallace L, Joplin R, Daikuhara Y, Ishii T, Kelly DA, Neuberger JM (1995) Characterization of biliary epithelial cells isolated from needle biopsies of human liver in the presence of hepatocyte growth factor. Am J Pathol 146:537–545

    PubMed  CAS  Google Scholar 

  28. Tanaka H, Nagaike K, Takeda N, Itoh H, Kohama K, Fukushima T, Miyata S, Uchiyama S, Uchinokura S, Shimomura T, Miyazawa K, Kitamura N, Yamada G, Kataoka H (2005) Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta. Mol Cell Biol 25:5687–5698

    Article  PubMed  CAS  Google Scholar 

  29. Taupin D, Podolsky DK (2003) Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4:721–732

    Article  PubMed  CAS  Google Scholar 

  30. Tsuneyama K, Harada K, Kono N, Sasaki M, Saito T, Gershwin ME, Ikemoto M, Arai H, Nakanuma Y (2002) Damaged interlobular bile ducts in primary biliary cirrhosis show reduced expression of glutathione-S-transferase-pi and aberrant expression of 4-hydroxynonenal. J Hepatol 37:176–183

    Article  PubMed  CAS  Google Scholar 

  31. West MD, Shay JW, Wright WE, Linskens MH (1996) Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence. Exp Gerontol 31:175–193

    Article  PubMed  CAS  Google Scholar 

  32. Yokomuro S, Tsuji H, Lunz JG 3rd, Sakamoto T, Ezure T, Murase N, Demetris AJ (2000) Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells. Hepatology 32:26–35

    Article  PubMed  CAS  Google Scholar 

  33. Zen Y, Harada K, Sasaki M, Tsuneyama K, Katayanagi K, Yamamoto Y, Nakanuma Y (2002) Lipopolysaccharide induces overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells: possible key phenomenon of hepatolithiasis. Am J Pathol 161:1475–1484

    PubMed  CAS  Google Scholar 

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Correspondence to Yasuni Nakanuma.

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Sasaki, M., Ikeda, H., Kataoka, H. et al. Augmented expression of hepatocytes growth factor activator inhibitor type 1 (HAI-1) in intrahepatic small bile ducts in primary biliary cirrhosis. Virchows Arch 449, 462–471 (2006). https://doi.org/10.1007/s00428-006-0257-7

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  • DOI: https://doi.org/10.1007/s00428-006-0257-7

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