Suppression of renal disease and mortality in the female NZBNZW F1 mouse model of systemic lupus erythematosus (SLE) by chenodeoxycholic acid

Abstract

The objective of this study was to examine the effects of ursodeoxycholic (UDCA) and chenodeoxycholic acid (CDCA) on autoimmune disease in the NZBNZW F¹ (B =W) mouse model of systemic lupus erythematosus (SLE).

The development of murine lupus was assessed in female B/W mice given UDCA or CDCA. At 6 week intervals mice were examined for weight change, albuminuria, anti-DNA antibody and total IgG levels. Morbidity and mortality were assessed daily. UDCA-and CDCA-treated mice were examined at 24 weeks of age for serum cytokines, lymphocyte phenotype, and in vitro cytokine production after immunization with DNP-KLH. Liver and kidneys were examined histopathologically.

The administration of UDCA and CDCA was tolerated without side effects. Weight gain in UDCA-or CDCA-treated and control mice was identical through 24 weeks of age. CDCA, but not UDCA, suppressed the development of renal disease. CDCA-treated B/W mice also had improved survival compared to UDCA-treated or control B/W mice. There were no significant effects of CDCA on anti-DNA antibodies, serum total IgG, or other immunologic parameters. CDCA-treated mice had lower serum IFN-g concentrations compared to control and UDCA-treated mice.

The bile acid, CDCA, significantly inhibited the development of renal disease and modestly prolonged lifespan in the female B/W mouse model of SLE. Suppression of glomerulonephritis was associated with lower serum IFNg concentrations. Further investigation is needed to verify potential mechanisms of action, but these findings suggest that bile acids may alter the development or progression of autoimmunity.

Keywords

bile acids treatment

Get full access to this article

View all access options for this article.

References

O'Farrelly C , Crispe NI . Prometheus through the looking glass: reflections on the hepatic immune system . Immunol Today. 1999; 20: 394–398 .

Sleisinger MH and Frodtran JS . In: Feldman M et al (eds). Gastrointestinal and Liver Disease, 6th edn. WB Saunders: Philadelphia, PA , 1998, pp 937–948, 1006-1006, 1018-1018 and 1275–1283.

Lacaille F , Paradis K . The immunosuppressive effect of ursodeoxycholic acid: a comparative in vitro on human peripheral blood mono-nuclear cells . Hepatology. 1993; 18: 165–172 .

Aouad K , Calmus Y , Nordlinger B , Myara A , Weill B , Poupon R . Immunosuppressive effects of endotoxin and bile acids in vivo in the rat . Eur J Clin Invest. 1996; 26: 45–48 .

Trauner M , Graziadei IW . Review article: mechanism of action and therapeutic application of ursodeoxycholic acid in chronic liver diseases . Aliment Pharmac Ther. 1999; 13: 979–995 .

Yoshikawa M , Tsujii T , Matsumura K et al. Immunomodulatory effects of ursodeoxycholic acid on immune responses . Hepatology. 1992; 16: 358–364 .

Calmus Y , Weill B , Ozier Y , Chereau C , Houssin D , Poupon R . Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse . Gastroenterology. 1992; 103: 617–621 .

Stiehl A . Disturbances of bile acid metabolism in cholestasis. In: Paumgartner G (ed). Clinics in Gastroenterology. Bile Acids. WB Saunders: London , 1977, pp 45–89.

Verrips A , Wevers RA , Van Engelen BGM et al. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis . Metabolism. 1999; 48: 233–238 .

10.

Van Heijst AFJ , Verrips A , Wevers RA , Cruysberg JRM , Renier WO , Tolboom JJM . Treatment and follow-up of children with cerebrotendinous xanthomatosis . Eur J Pediatr. 1998; 157: 313–316 .

11.

Calmus Y , Guechot J , Podevin P , Bonnefis MT , Giboudeau J , Poupon R . Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-a production by monocytes . Hepatology. 1992; 16: 719–723 .

12.

Filaci G , Pelli N , Sacco T et al. S-adenosil-L-methionine is able to reverse the immunosuppressive effects of chenodeoxycholic acid in vitro . Int J Immunopharmac. 1997; 19: 157–165 .

13.

American College of Rheumatology ad hoc Committee on SLE guidelines . Guidelines for referral and management of systemic lupus erythematosus in adults . Arthrit Rheum. 1999; 42: 1785–1796 .

14.

Altomonte L , Zoli A , Sommela L , Palumbo P , Greco AV , Magaro M . Concentration of serum bile acids as an index of hepatic damage in systemic lupus erythematosus . Clin Rheumatol. 1984; 3: 209–212 .

15.

Matsumoto T , Yoshimine T , Shimouchi K et al. The liver in systemic lupus erythematosus: pathologic analysis of 52 cases and review of Japanese autopsy registry data . Human Pathol. 1992; 23: 1151–1158 .

16.

Mackay IR . Hepatic disease and systemic lupus erythematosus: coincidence or convergence. In: Lahita RG (ed). Systemic Lupus Erythematosus, 3rd edn. Academic Press: San Diego, CA , 1999, pp 747–763.

17.

Iliffe GD , Naidoo S , Hunter T . Primary biliary cirrhosis associated with features of systemic lupus erythematosus . Dig Dis Sci. 1982; 27: 274–278 .

18.

Schifter T , Lewinski UH . Primary biliary cirrhosis and systemic lupus erythematosus. A rare association . Clin Exp Rheumatol. 1997; 15: 313–314 .

19.

Michel F , Toussirot E , Wendling D . Primary biliary cirrhosis and systemic lupus erythematosus. A new case report . Rev Rheum Engl Edn. 1998; 65(7–9): 504–507 .

20.

Islam S , Riordan JW , McDonald JA . Case report: a rare association of primary biliary cirrhosis and systemic lupus erythematosus and a review of literature . J Gastroenterol Hepatol. 1999; 14: 431–435 .

21.

Culp K , Fleming C , Duffy J et al. Autoimmune associations in primary biliary cirrhosis . Mayo Clin Proc 1982, 57: 365–370 .

22.

Theofilopoulos AN . Murine models of lupus. In: Lahita RG (ed). Systemic Lupus Erythematosus, 2nd edn. Churchill Livingstone: New York , 1992, pp 121–194.

23.

McMurray RW , Elbourne KB , Lagoo A , Lal S . Mycophenolate mofetil suppresses autoimmunity and mortality in the female NZBNZB F1 mouse model of systemic lupus erythematosus . J Rheumatol. 1998; 25: 2364–2370 .

24.

Yellin TO , Klaiber MS , Webb E . Lithogenic effects of cholic and chenodeoxycholic acid in the cholesterol fed mouse . Biochem Biophys Acta. 1973; 320: 478–485 .

25.

Uchida K , Akiyoshi T , Igimi H , Takase H , Nomura Y , Ishihara S . Differential effects of ursodeoxycholic acid and ursocholic acid on the formation of biliary cholesterol crystals in mice . Lipids. 1991; 26: 526–530 .

26.

Zukowski Th , Jorgenson RA , Dickson ER , Lindor KD . Auto-immune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy . Am J Gastroenterol. 1998; 93: 958–961 .

27.

Hoffman AF , Roda A . Physiochemical properties of bile acids and their relationship to biochemical properties: an overview of the problem . J Lipid Res. 1984; 25: 1477–1489 .

28.

McMurray RW , Hoffman RW , Nelson W , Walker SE . Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus <Eth> analyses of strain, gender, and age effects . Clin Immunol Immunopathol. 1997; 84: 260–268 .

29.

Haas C . IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZBNZW) F1 mice . J Immunol. 1998; 160: 3713–3718 .

30.

Haas C . IFN-gamma is essential for the development of autoimmune glomerulonephritis in MRL/lpr mice . J Immunol. 1997; 158: 5484–5491 .

31.

Ozmen L . Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis Eur J Immunol. 1995; 25: 6–12 .

32.

Podevin P , Rosmorduc O , Conti F , Calmus Y , Meier PJ , Poupon R . Bile acids modulate the interferon signalling pathway . Hepatology. 1999; 29: 1840–1847 .

33.

Hardy KJ , Sawada T . Human g interferon strongly upregulates its own gene expression in peripheral blood lymphocytes . J Exp Med. 1989; 170: 1021–1026 .