Digestive Diseases and Sciences

, Volume 41, Issue 7, pp 1487–1493 | Cite as

Ursodeoxycholic acid corrects defective natural killer activity by inhibiting prostaglandin E2 production in primary biliary cirrhosis

  • Youichi Nishigaki
  • Hiroo Ohnishi
  • Hisataka Moriwaki
  • Yasutoshi Muto
Liver: Cirrhosis, Fibrosis, Portal Hypertension, And Transplantation


We evaluated the effect of ursodeoxycholic acid on the defective natural killer activity in primary biliary cirrhosis. Administration of ursodeoxycholic acid (600 mg daily) for one month significantly increased natural killer activity in patients with primary biliary cirrhosis (P<0.05). Ursodeoxycholic acid also enhanced thein vitro natural killer activity of lymphocytes from healthy volunteers, while other hydrophobic bile acids depressed it. Furthermore, ursodeoxycholic acid reduced the prostaglandin E2 concentration in culture supernatants of lymphocytes from healthy volunteers to a lower level than that in cultures incubated with chenodeoxycholic acid (P<0.05) or control cultures (P<0.01). Ursodeoxycholic acid normalized the defective natural killer activity in primary biliary cirrhosis by reducing the levels of other hydrophobic bile acids and inhibiting prostaglandin E2 production, suggesting that it may be a useful immunomodulating agent for primary biliary cirrhosis.

Key words

ursodeoxycholic acid primary biliary cirrhosis natural killer activity immunomodulation 


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  1. 1.
    James SP, Jones EA: Abnormal natural killer cytotoxicity in primary biliary cirrhosis: Evidence for a functional deficiency of cytolytic effector cells. Gastroenterology 89:165–171, 1985Google Scholar
  2. 2.
    Matheson DS, Green BJ, Minuk GY: Natural killer-cell activity and the response to interferons alpha, beta, and gamma in patients with primary biliary cirrhosis. J Allergy Clin Immunol 84:214–218, 1989Google Scholar
  3. 3.
    Abruzzo LV, Rowley DA: Homeostasis of the antibody response: immunoregulation by NK cells. Science 222:581–585, 1983Google Scholar
  4. 4.
    Pope RM, McChesney L, Stebbing N, Goldstein L, Talal N: Regulation of T cell proliferation by cloned interferon-α mediated by Leu-11b-positive cells. J Immunol 135:4048–4053, 1985Google Scholar
  5. 5.
    Tomoda T, Moriwaki H, Ohnishi H, Tomita E, Takai T, Muto Y, Kumada T, Okuyama S: Therapeutic effect of ursodeoxycholic acid on sulpyrine-induced intrahepatic cholestasis, a case report. Jpn J Gastroenterol 81(11):2821–2825, 1984 (in Japanese)Google Scholar
  6. 6.
    Poupon R, Chrétien Y, Poupon RE, Ballet F, Calmus Y, Darnis F: Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 11:834–836, 1987Google Scholar
  7. 7.
    Chrétien Y, Poupon R, Gherardt MF, Chazouilleres O, Labbe D, Myara A, Trivin F: Bile acid glycine and taurine conjugates in serum of patients with primary biliary cirrhosis: Effect of ursodeoxycholic treatment. Gut 30:1110–1115, 1989Google Scholar
  8. 8.
    Renner EL, Lake JR, Cragoe EJ, Dyke RWV, Scharschmidt BF: Ursodeoxycholic acid choleresis: relationship to biliary HCO3 and effects of Na+-H+ exchange inhibitors. Am J Physiol 254:232–241, 1988Google Scholar
  9. 9.
    Heuman DM, Pandak WM, Hylemon PB, Vlahcevic ZR: Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts:In vitro studies in rat hepatocytes and human erythrocytes. Hepatology 14:920–926, 1991Google Scholar
  10. 10.
    Leuschner U, Fischer H, Kurtz W, Güldütuna S, Hübner K, Hellstern A, Gatzen M, Leuschner M: Ursodeoxycholic acid in primary biliary cirrhosis: Results of a controlled double-blind trial. Gastroenterology 97:1268–1274, 1989Google Scholar
  11. 11.
    Okuyama S, Kokubun N, Higashidate S, Uemura D, Hirata Y: A new analytical method of individual bile acids using high performance liquid chromatography and immobilized 3α-hydroxysteroid dehydrogenase in column form. Chem Lett 1443–1446, 1979Google Scholar
  12. 12.
    Yamada G, Hyodo I, Tobe K, Mizuno M, Nishihara T, Kobayashi T, Nagashima H: Ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelial in primary biliary cirrhosis. Hepatology 6:385–391, 1986Google Scholar
  13. 13.
    Hoffmann RM, Pape GR, Spengler U, Rieber EP, Eisenburg J, Dohrmann J, Paumgartner G, Riethmüller G: Clonal analysis of liver-derived T cells of patients with primary biliary cirrhosis. Clin Exp Immunol 76:210–215, 1989Google Scholar
  14. 14.
    Poupon RE, Balkau B, Eschwege E, Poupon R: A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 324:1548–1554, 1991Google Scholar
  15. 15.
    Batta AK, Salen G, Mirchandani R, Tint GS, Shefer S, Batta M, Abroon J, O'Brien CB, Senior JR: Effect of long-term treatment with ursodiol on clinical and biochemical features and biliary bile acid metabolism in patients with primary biliary cirrhosis. Am J Gastroenterol 88:691–700, 1993Google Scholar
  16. 16.
    Terasaki S, Nakanuma Y, Ogino H, Unoura M, Kobayashi K: Hepatocellular and biliary expression of HLA antigens in primary biliary cirrhosis before and after ursodeoxycholic acid therapy. Am J Gastroenterol 86:1194–1199, 1991Google Scholar
  17. 17.
    Friman S, Persson H, Schersten T, Svanvik J, Karlberg I: Adjuvant treatment with ursodeoxycholic acid reduces acute rejection after liver transplantation. Transplant Proc 24:389–390, 1992Google Scholar
  18. 18.
    Friman S, Mjornstedt L, Persson H, Karlberg I, Olausson M: Ursodeoxycholic acid reduces acute rejection in heart allografted rats. Transplant Proc 24:344–345, 1992Google Scholar
  19. 19.
    Essell JH, Thompson JM, Harman GS, Halvorson RD, Snyder MJ, Callander NS, Clement DJ: Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant 10:367–372, 1992Google Scholar
  20. 20.
    Fried RH, Murakami CS, Fisher LD, Willson RA, Sullivan KM, McDonald GB: Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver. Ann intern Med 116:624–629, 1992Google Scholar
  21. 21.
    Batta AK, Arora R, Salen G, Tint GS, Eskreis D, Katz S: Characterization of serum and urinary bile acids in patients with primary biliary cirrhosis by gas-liquid chromatography-mass spectrometry: Effect of ursodeoxycholic treatment. J Lipid Res 30:1953–1962, 1989Google Scholar
  22. 22.
    Leung KH: Inhibition of human NK cell and LAK cell cytotoxicity and differentiation by PGE2. Cell Immunol 123:384–395, 1989Google Scholar
  23. 23.
    Garcia-Penarrubia P, Bankhurst AD, Koster FT: Prostaglandins from human T suppressor/cytotoxic cells modulate natural killer antibacterial activity. J Exp Med 170:601–606, 1989Google Scholar
  24. 24.
    Gianni L, Dipadova F, Zuin M, Pdda M: Bile acid-induced inhibition of the lymphoproliferative response to phytohemagglutinin and pokeweed mitogen: Anin vitro study. Gastroenterology 78:231–235, 1980Google Scholar
  25. 25.
    Calmus Y, Weill B, Ozier Y, Chereau C, Houssin D, Poupon R: Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse. Gastroenterology 103:617–621, 1992Google Scholar
  26. 26.
    Chiricolo M, Lenzi M, Bianchi F, Franceschi C, Bartolini G, Orlandi M, Tomasi V, Licastro F: Immune dysfunction in primary biliary cirrhosis. II. Increased production of prostaglandin E. Scand J Immunol 30:363–367, 1989Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Youichi Nishigaki
    • 1
  • Hiroo Ohnishi
    • 1
  • Hisataka Moriwaki
    • 1
  • Yasutoshi Muto
    • 1
  1. 1.First Department of Internal MedicineGifu University School of MedicineGifuJapan

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