Semin Liver Dis 2005; 25(3): 251-264
DOI: 10.1055/s-2005-916318
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Immunophysiology of Biliary Epithelium

Giammarco Fava1 , Shannon Glaser2 , 3 , Heather Francis3 , Gianfranco Alpini1 , 2 , 4
  • 1Department of Medical Physiology, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine
  • 2Department of Medicine, Scott & White Hospital and The Texas A&M University System HSC, COM
  • 3Division of R&E, Scott & White Hospital and The Texas A&M University System HSC, COM
  • 4Professor of Medicine and Medical Physiology, and Dr. Nicholas C. Hightower Centennial Chair of , Central Texas Veterans Healthcare System, Temple, Texas
Further Information

Publication History

Publication Date:
06 September 2005 (online)

ABSTRACT

The immune system maintains the homeostasis of the biliary epithelium, where bile and cholangiocytes play an important role in modulating immune responses. Furthermore, cholangiocytes represent the target of the immune system in several hepatobiliary diseases (e.g., primary biliary cirrhosis). This article is organized into two parts. The first section reviews the role of cholangiocytes in the immune defense and the mechanisms by which cholangiocytes regulate immune responses. The expression of adhesion molecules on the cholangiocyte surface allows the interaction with immune cells, thus localizing and modulating the intensity of the immune reactions. Moreover, cholangiocytes secrete immunoglobulins, cytokines, and other mediators, which affect the functions of the surrounding liver cells, as well the cholangiocytes themselves. Cholangiocytes express major histocompatibility complex molecules, and thereby could act as antigen-presenting cells. In the second section, we describe how cytokines and inflammatory mediators modulate cholangiocyte function such as proliferation, apoptosis, secretion, and malignant transformation.

REFERENCES

  • 1 Alpini G, McGill J M, LaRusso N F. The pathobiology of biliary epithelia.  Hepatology. 2002;  35 1256-1268
  • 2 Roberts S K, Ludwig J, LaRusso N F. The pathobiology of biliary epithelia.  Gastroenterology. 1997;  112 269-279
  • 3 Alpini G, Prall R T, LaRusso N F. The pathobiology of biliary epithelia. In: Arias IM, Boyer JL, Chisari FV, et al The Liver: Biology and Pathobiology, 4th ed. Philadelphia; Lippincott Williams & Wilkins 2001: 421-435
  • 4 Nathanson M H, Boyer J L. Mechanisms and regulation of bile secretion.  Hepatology. 1991;  14 551-566
  • 5 Boyer J L. Bile duct epithelium: frontiers in transport physiology.  Am J Physiol. 1996;  270 G1-G5
  • 6 Masyuk A I, Marinelli R A, LaRusso N F. Water transport by epithelia of the digestive tract.  Gastroenterology. 2002;  122 545-562
  • 7 Kanz M F, Gunasena G H, Kaphalia L et al.. A minimally toxic dose of methylene dianiline injures biliary epithelial cells in rats.  Toxicol Appl Pharmacol. 1998;  150 414-426
  • 8 Kanz M F, Dugas T R, Liu H, Santa Cruz V. Glutathione depletion exacerbates methylenedianiline toxicity to biliary epithelial cells and hepatocytes in rats.  Toxicol Sci. 2003;  74 447-456
  • 9 Reynoso-Paz S, Coppel R L, Mackay I R et al.. The immunobiology of bile and biliary epithelium.  Hepatology. 1999;  30 351-357
  • 10 Yamagiwa Y, Patel T. Cytokine regulation of cholangiocyte growth. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 227-234
  • 11 Kanno N, LeSage G, Glaser S et al.. Functional heterogeneity of the intrahepatic biliary epithelium.  Hepatology. 2000;  31 555-561
  • 12 Steiner J W, Carruthers J S, Kalifat S R. The ductular cell reaction of rat liver in extrahepatic cholestasis. I. Proliferated biliary epithelial cells.  Exp Mol Pathol. 1962;  1 162-185
  • 13 Glaser S S, Francis H, Marzioni M et al.. Functional heterogeneity of the intrahepatic biliary epithelium. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 245-254
  • 14 Alpini G, Roberts S, Kuntz S M et al.. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver.  Gastroenterology. 1996;  110 1636-1643
  • 15 Alpini G, Glaser S, Robertson W et al.. Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion.  Am J Physiol. 1997;  272 G1064-G1074
  • 16 Benedetti A, Bassotti C, Rapino K et al.. A morphometric study of the epithelium lining the rat intrahepatic biliary tree.  J Hepatol. 1996;  24 335-342
  • 17 Alpini G, Glaser S S, Ueno Y et al.. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation.  Am J Physiol. 1998;  274 G767-G775
  • 18 LeSage G D, Glaser S S, Marucci L et al.. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver.  Am J Physiol. 1999;  276 G1289-G1301
  • 19 Marzioni M, Glaser S S, Francis H et al.. Functional heterogeneity of cholangiocytes.  Semin Liver Dis. 2002;  22 227-240
  • 20 Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study.  Gastroenterology. 1996;  111 1118-1124
  • 21 Gaudio E, Onori P, Franchitto A et al.. Vascularization of the intrahepatic biliary tree and its role in the regulation of cholangiocyte growth. In: Alpini G, Alvaro D, Marzioni M et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 41-50
  • 22 Vierling J, Braun M, Wang H. Immunopathogenesis of vanishing bile duct syndromes. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 330-356
  • 23 Tsukahara A, Seki S, Iiai T et al.. Mouse liver T cells: their change with aging and in comparison with peripheral T cells.  Hepatology. 1997;  26 301-309
  • 24 Naito M, Hasegawa G, Ebe Y, Yamamoto T. Differentiation and function of Kupffer cells.  Med Electron Microsc. 2004;  37 16-28
  • 25 Delves P J, Roitt I M. The immune system. First of two parts.  N Engl J Med. 2000;  343 37-49
  • 26 Delves P J, Roitt I M. The immune system. Second of two parts.  N Engl J Med. 2000;  343 108-117
  • 27 Klein J, Sato A. The HLA system. First of two parts.  N Engl J Med. 2000;  343 702-709
  • 28 Klein J, Sato A. The HLA system. Second of two parts.  N Engl J Med. 2000;  343 782-786
  • 29 Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity.  Nat Immunol. 2004;  5 971-974
  • 30 Janeway Jr C A, Bottomly K. Signals and signs for lymphocyte responses.  Cell. 1994;  76 275-285
  • 31 Chakrabarti D, Hultgren B, Stewart T A. IFN-alpha induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B7.2  J Immunol. 1996;  157 522-528
  • 32 Demetris A J, Lunz III J G, Subbotin V et al.. Participation of cytokines and growth factors in biliary epithelial proliferation and mito-inhibition during ductular reactions. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 167-191
  • 33 Torok N J, Gores G J. Apoptosis of biliary epithelial cells. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia Georgetown, TX; Landes Bioscience 2004: 219-226
  • 34 Alvarez F, Schwarz K. Immune diseases of the liver and biliary tract.  J Pediatr Gastroenterol Nutr. 2002;  35(suppl 1) S39-S43
  • 35 Ueno Y, Ishii M, Yahagi K et al.. Fas-mediated cholangiopathy in the murine model of graft versus host disease.  Hepatology. 2000;  31 966-974
  • 36 Ueno Y. Fas-mediated cholangiopathy in a murine model of graft-versus-host disease. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 235-244
  • 37 Popper H, Kent G, Stein R. Ductular cell reaction in the liver in hepatic injury.  J Mt Sinai Hosp N Y. 1957;  24 551-556
  • 38 Lazaridis K N, Strazzabosco M, LaRusso N F. The cholangiopathies: disorders of biliary epithelia.  Gastroenterology. 2004;  127 1565-1577
  • 39 Schuppan  et al.. Fibrogenesis in PBC. In: Lindor KD, Heathcote J, Poupon R Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment. Dordrecht, The Netherlands; Kluwer Academic Press 1998: 64-75
  • 40 Desmet V J. Modulation of the liver in cholestasis.  J Gastroenterol Hepatol. 1992;  7 313-323
  • 41 Roskams T, Desmet V. Ductular reaction and its diagnostic significance.  Semin Diagn Pathol. 1998;  15 259-269
  • 42 Desmet V J. Ludwig symposium on biliary disorders-part I. Pathogenesis of ductal plate abnormalities.  Mayo Clin Proc. 1998;  73 80-89
  • 43 Auth M K, Keitzer R A, Scholz M et al.. Establishment and immunological characterization of cultured human gallbladder epithelial cells.  Hepatology. 1993;  18 546-555
  • 44 Hreha G, Jefferson D M, Yu C H et al.. Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity.  Hepatology. 1999;  30 358-371
  • 45 Wu C T, Davis P A, Luketic V A, Gershwin M E. A review of the physiological and immunological functions of biliary epithelial cells: targets for primary biliary cirrhosis, primary sclerosing cholangitis and drug-induced ductopenias.  Clin Dev Immunol. 2004;  11 205-213
  • 46 Leon M P, Kirby J A, Gibbs P et al.. Immunogenicity of biliary epithelial cells: study of the expression of B7 molecules.  J Hepatol. 1995;  22 591-595
  • 47 Morita M, Watanabe Y, Akaike T. Inflammatory cytokines up-regulate intercellular adhesion molecule-1 expression on primary cultured mouse hepatocytes and T-lymphocyte adhesion.  Hepatology. 1994;  19 426-431
  • 48 Leon M P, Bassendine M F, Wilson J L et al.. Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells.  Hepatology. 1996;  24 561-567
  • 49 Sugiura H, Nakanuma Y. Secretory component and immunoglobulins in the intrahepatic biliary tree and peribiliary gland in normal livers and hepatolithiasis.  Gastroenterol Jpn. 1989;  24 308-314
  • 50 Scholz M, Cinatl J, Blaheta R A et al.. Expression of human leukocyte antigens class I and class II on cultured biliary epithelial cells after cytomegalovirus infection.  Tissue Antigens. 1997;  49 640-643
  • 51 Ayres R C, Neuberger J M, Shaw J et al.. Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines.  Gut. 1993;  34 1245-1249
  • 52 Cruickshank S M, Southgate J, Selby P J, Trejdosiewicz L K. Expression and cytokine regulation of immune recognition elements by normal human biliary epithelial and established liver cell lines in vitro.  J Hepatol. 1998;  29 550-558
  • 53 Leon M P, Bassendine M F, Gibbs P et al.. Immunogenicity of biliary epithelium: study of the adhesive interaction with lymphocytes.  Gastroenterology. 1997;  112 968-977
  • 54 Hahn W C, Burakoff S J, Bierer B E. Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58.  J Immunol. 1993;  150 2607-2619
  • 55 Guo Y, Wu Y, Shinde S et al.. Identification of a costimulatory molecule rapidly induced by CD40L as CD44H.  J Exp Med. 1996;  184 955-961
  • 56 Sempowski G D, Chess P R, Moretti A J et al.. CD40 mediated activation of gingival and periodontal ligament fibroblasts.  J Periodontol. 1997;  68 284-292
  • 57 Karmann K, Hughes C C, Fanslow W C, Pober J S. Endothelial cells augment the expression of CD40 ligand on newly activated human CD4+ T cells through a CD2/LFA-3 signaling pathway.  Eur J Immunol. 1996;  26 610-617
  • 58 Morland C M, Fear J, McNab G, Joplin R, Adams D H. Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro.  Proc Assoc Am Physicians. 1997;  109 372-382
  • 59 Yasoshima M, Kono N, Sugawara H et al.. Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study.  Lab Invest. 1998;  78 89-100
  • 60 Matsumoto K, Fujii H, Michalopoulos G et al.. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro.  Hepatology. 1994;  20 376-382
  • 61 Bour E S, Ward L K, Cornman G A, Isom H C. Tumor necrosis factor-alpha-induced apoptosis in hepatocytes in long-term culture.  Am J Pathol. 1996;  148 485-495
  • 62 Fabris L, Strazzabosco M, Crosby H A et al.. Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations.  Am J Pathol. 2000;  156 1599-1612
  • 63 Rockey D C, Fouassier L, Chung J J et al.. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells.  Hepatology. 1998;  27 472-480
  • 64 Wang H, Hreha G, Vierling J. Proinflammatory cytokines and lipopolysaccharide induce chemokine and cytokine expression by immortalized biliary epithelial cells through nuclear factor kappa B.  Hepatology. 2001;  34 A369
  • 65 Wang H, Hreha G, Vierling J. Chemokine receptor expression by biliary epithelial cells during evolution of nonsuppurative destructive cholangitis in murine chronic graft-vs-host disease.  Hepatology. 2001;  34 A355
  • 66 Wang H, Hreha G, Ouyang Y et al.. Mouse intrahepatic immortalized biliary epithelial cells exhibit innate immune response functions of macrophages.  Hepatology. 2001;  34 A368
  • 67 Harada K, Ohira S, Isse K et al.. Lipopolysaccharide activates nuclear factor-kappaB through toll-like receptors and related molecules in cultured biliary epithelial cells.  Lab Invest. 2003;  83 1657-1667
  • 68 Hiramatsu K, Harada K, Tsuneyama K et al.. Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis.  J Hepatol. 2000;  33 9-18
  • 69 Saidman S L, Duquesnoy R J, Zeevi A et al.. Recognition of major histocompatibility complex antigens on cultured human biliary epithelial cells by alloreactive lymphocytes.  Hepatology. 1991;  13 239-246
  • 70 Himeno H, Saibara T, Onishi S et al.. Administration of interleukin-2 induces major histocompatibility complex class II expression on the biliary epithelial cells, possibly through endogenous interferon-gamma production.  Hepatology. 1992;  16 409-417
  • 71 Markus B H, Duquesnoy R J, Blaheta R A et al.. Role of HLA antigens in liver transplantation with special reference to cellular immune reactions.  Langenbecks Arch Surg. 1998;  383 87-94
  • 72 Savage C O, Brooks C J. Human vascular endothelial cells do not induce anergy in allogeneic CD4+ T cells unless costimulation is prevented.  Transplantation. 1995;  60 734-740
  • 73 Lombardi G, Sidhu S, Batchelor R, Lechler R. Anergic T cells as suppressor cells in vitro.  Science. 1994;  264 1587-1589
  • 74 Kamihira T, Shimoda S, Nakamura M et al.. Biliary epithelial cells regulate autoreactive T cells: implications for biliary-specific diseases.  Hepatology. 2005;  41 151-159
  • 75 Iwai Y, Terawaki S, Ikegawa M et al.. PD-1 inhibits antiviral immunity at the effector phase in the liver.  J Exp Med. 2003;  198 39-50
  • 76 Sung J Y, Costerton J W, Shaffer E A. Defense system in the biliary tract against bacterial infection.  Dig Dis Sci. 1992;  37 689-696
  • 77 Sung J Y, Shaffer E A, Olson M E et al.. Bacterial invasion of the biliary system by way of the portal-venous system.  Hepatology. 1991;  14 313-317
  • 78 Nakanuma Y, Hoso M, Sanzen T, Sasaki M. Microstructure and development of the normal and pathologic biliary tract in humans, including blood supply.  Microsc Res Tech. 1997;  38 552-570
  • 79 Hopf U, Moller B, Stemerowicz R et al.. Relation between Escherichia coli R(rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis.  Lancet. 1989;  2 1419-1422
  • 80 Nagura H, Smith P D, Nakane P K, Brown W R. IGA in human bile and liver.  J Immunol. 1981;  126 587-595
  • 81 Lemaitre-Coelho I, Jackson G D, Vaerman J P. Rat bile as a convenient source of secretory IgA and free secretory component.  Eur J Immunol. 1977;  7 588-590
  • 82 Russell M W, Brown T A, Mestecky J. Role of serum IgA. Hepatobiliary transport of circulating antigen.  J Exp Med. 1981;  153 968-976
  • 83 Takahashi I, Nakane P K, Brown W R. Ultrastructural events in the translocation of polymeric IgA by rat hepatocytes.  J Immunol. 1982;  128 1181-1187
  • 84 Delacroix D L, Courtoy P J, Rahier J et al.. Localization and serum concentration of secretory component during massive necrosis of human liver.  Gastroenterology. 1984;  86 521-531
  • 85 Daniels C K, Schmucker D L. Secretory component-dependent binding of immunoglobulin A in the rat, monkey and human: a comparison of intestine and liver.  Hepatology. 1987;  7 517-521
  • 86 Aagaard B D, Heyworth M F, Oesterle A L et al.. Intestinal immunisation with Escherichia coli protects rats against Escherichia coli induced cholangitis.  Gut. 1996;  39 136-140
  • 87 Harmatz P R, Kleinman R E, Bunnell B W et al.. Hepatobiliary clearance of IgA immune complexes formed in the circulation.  Hepatology. 1982;  2 328-333
  • 88 Peppard J V, Orlans E, Andrew E, Payne A W. Elimination into bile of circulating antigen by endogenous IgA antibody in rats.  Immunology. 1982;  45 467-472
  • 89 Mostov K E. Transepithelial transport of immunoglobulins.  Annu Rev Immunol. 1994;  12 63-84
  • 90 Mazanec M B, Kaetzel C S, Lamm M E et al.. Intracellular neutralization of Sendai and influenza viruses by IgA monoclonal antibodies.  Adv Exp Med Biol. 1995;  371A 651-654
  • 91 Mazanec M B, Coudret C L, Fletcher D R. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies.  J Virol. 1995;  69 1339-1343
  • 92 Manning R J, Walker P G, Carter L et al.. Studies on the origins of biliary immunoglobulins in rats.  Gastroenterology. 1984;  87 173-179
  • 93 Jackson G D, Walker P G. The transient appearance of IgM antibodies in the bile of rats injected with Salmonella enteritidis .  Immunol Lett. 1983;  7 41-45
  • 94 Nakanuma Y, Katayanagi K, Terada T, Saito K. Intrahepatic peribiliary glands of humans. I. Anatomy, development and presumed functions.  J Gastroenterol Hepatol. 1994;  9 75-79
  • 95 Saito K, Nakanuma Y. Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study.  J Hepatol. 1992;  15 147-153
  • 96 Saito J M, Maher J J. Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant.  Gastroenterology. 2000;  118 1157-1168
  • 97 Park J, Tadlock L, Gores G J, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line.  Hepatology. 1999;  30 1128-1133
  • 98 Spirli C, Nathanson M H, Fiorotto R et al.. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium.  Gastroenterology. 2001;  121 156-169
  • 99 Spirli C, Fabris L, Duner E et al.. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes.  Gastroenterology. 2003;  124 737-753
  • 100 Marra F. Chemokines in liver inflammation and fibrosis.  Front Biosci. 2002;  7 d1899-d1914
  • 101 Jaiswal M, LaRusso N F, Gores G J. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis.  Am J Physiol. 2001;  281 G626-G634
  • 102 Park J, Gores G J, Patel T. Lipopolysaccharide induces cholangiocyte proliferation via an interleukin-6-mediated activation of p44/p42 mitogen-activated protein kinase.  Hepatology. 1999;  29 1037-1043
  • 103 Yokomuro S, Tsuji H, Lunz III J G et al.. 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. 2000;  32 26-35
  • 104 Liu Z, Sakamoto T, Ezure T et al.. Interleukin-6, hepatocyte growth factor, and their receptors in biliary epithelial cells during a type I ductular reaction in mice: interactions between the periductal inflammatory and stromal cells and the biliary epithelium.  Hepatology. 1998;  28 1260-1268
  • 105 Saperstein L A, Jirtle R L, Farouk M et al.. Transforming growth factor-beta 1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat.  Hepatology. 1994;  19 412-417
  • 106 Tadlock L, Yamagiwa Y, Hawker J et al.. Transforming growth factor-beta inhibition of proteasomal activity: a potential mechanism of growth arrest.  Am J Physiol Cell Physiol. 2003;  285 C277-C285
  • 107 Miyazaki M, Ohashi R, Tsuji T et al.. Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1.  Biochem Biophys Res Commun. 1998;  246 873-880
  • 108 Afford S C, Ahmed-Choudhury J, Randhawa S et al.. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells.  FASEB J. 2001;  15 2345-2354
  • 109 Ahn E Y, Pan G, Vickers S M, McDonald J M. IFN-gamma upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma.  Int J Cancer. 2002;  100 445-451
  • 110 Gapany C, Zhao M, Zimmermann A. The apoptosis protector, bcl-2 protein, is downregulated in bile duct epithelial cells of human liver allografts.  J Hepatol. 1997;  26 535-542
  • 111 Utaisincharoen P, Tangthawornchaikul N, Ubol S et al.. TNF-alpha induces caspase 3 (CPP 32) dependent apoptosis in human cholangiocarcinoma cell line.  Southeast Asian J Trop Med Public Health. 2000;  31(suppl 1) 167-170
  • 112 Sherlock S. Overview of chronic cholestatic conditions in adults: terminology and definitions.  Clin Liver Dis. 1998;  2 217-233 vii
  • 113 Spirli C, Okolicsanyi L, Strazzabosco M. Effects of cytokines and nitric oxide on bicarbonate secretion by cholangiocytes. In: Alpini G, Alvaro D, Marzioni M, et al The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 81-88
  • 114 Gaweco A S, Otto G, Otto H F et al.. Distinct intragraft cytokine gene expression patterns during acute hepatic rejection under cyclosporine versus FK 506 primary immunosuppression.  Transplant Proc. 1994;  26 3111-3113
  • 115 McGill J M, Yen M S, Cummings O W et al.. Interleukin-5 inhibition of biliary cell chloride currents and bile flow.  Am J Physiol Gastrointest Liver Physiol. 2001;  280 G738-G745
  • 116 Trauner M. When bile ducts say NO: the good, the bad, and the ugly.  Gastroenterology. 2003;  124 847-851
  • 117 Buttery L D, Evans T J, Springall D R et al.. Immunochemical localization of inducible nitric oxide synthase in endotoxin-treated rats.  Lab Invest. 1994;  71 755-764
  • 118 Trauner M, Nathanson M H, Rydberg S A et al.. Endotoxin impairs biliary glutathione and HCO3- excretion and blocks the choleretic effect of nitric oxide in rat liver.  Hepatology. 1997;  25 1184-1191
  • 119 Xia X, Roundtree M, Merikhi A et al.. Degradation of the apical sodium-dependent bile acid transporter by the ubiquitin-proteasome pathway in cholangiocytes.  J Biol Chem. 2004;  279 44931-44937
  • 120 Gores G J. Cholangiocarcinoma: current concepts and insights.  Hepatology. 2003;  37 961-969
  • 121 Jaiswal M, LaRusso N F, Shapiro R A et al.. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes.  Gastroenterology. 2001;  120 190-199
  • 122 Torok N J, Higuchi H, Bronk S, Gores G J. Nitric oxide inhibits apoptosis downstream of cytochrome C release by nitrosylating caspase 9.  Cancer Res. 2002;  62 1648-1653
  • 123 Zhang Z, Lai G H, Sirica A E. Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation.  Hepatology. 2004;  39 1028-1037
  • 124 Nzeako U C, Guicciardi M E, Yoon J H et al.. COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells.  Hepatology. 2002;  35 552-559
  • 125 Tanaka S, Sugimachi K, Shirabe K et al.. Expression and antitumor effects of TRAIL in human cholangiocarcinoma.  Hepatology. 2000;  32 523-527
  • 126 Utaisincharoen P, Ubol S, Tangthawornchaikul N et al.. Binding of tumour necrosis factor-alpha (TNF-alpha) to TNF-RI induces caspase(s)-dependent apoptosis in human cholangiocarcinoma cell lines.  Clin Exp Immunol. 1999;  116 41-47
  • 127 Sirica A E, Lai G H, Endo K et al.. Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets.  Semin Liver Dis. 2002;  22 303-313
  • 128 Vierling J M. Animal models of autoimmune liver diseases. In: Gershwin ME, Vierling JM, Manns MP Immunology of the Liver. Philadelphia; Hanley & Belfus 2002: 200-230

Gianfranco AlpiniPh.D. 

The Texas A&M University System, HSC COM, and Central Texas Veterans HCS

MRB, 702 South West H.K. Dodgen Loop

Temple, Texas 76504

Email: galpini@tamu.edu

Email: galpini@medicine.tamu.edu

    >