Therapeutic effects of roxithromycin in interleukin-10-deficient colitis
Hiroshi Tamagawa MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorTakachika Hiroi DDS, PhD
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorTsunekazu Mizushima MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorToshinori Ito MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorHikaru Matsuda MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorCorresponding Author
Hiroshi Kiyono DDS, PhD
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
CREST, Japan Science and Technology Agency, Tokyo, Japan
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-Tokyo, 108-8639, JapanSearch for more papers by this authorHiroshi Tamagawa MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorTakachika Hiroi DDS, PhD
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorTsunekazu Mizushima MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorToshinori Ito MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorHikaru Matsuda MD, PhD
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
Search for more papers by this authorCorresponding Author
Hiroshi Kiyono DDS, PhD
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
CREST, Japan Science and Technology Agency, Tokyo, Japan
Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-Tokyo, 108-8639, JapanSearch for more papers by this authorAbstract
Background: A limited number of therapeutic strategies are currently available to treat patients with inflammatory bowel disease (IBD). Interleukin-10 (IL-10)—deficient mice, well characterized as an experimental model of IBD, develop severe chronic colitis because of aberrant Th1 responses. Roxithromycin (RXM), a macrolide antibiotic, has received attention because it offers not only antibacterial but also immunosuppressive effects. We examined the immunosuppressive effect of RXM on the development of IBD.
Methods: To test the efficacy of short-term administration of RXM, elder IL-10-deficient mice (16–20 weeks old) with established colitis were orally treated for 10 days with RXM (20 mg/kg per day). To test the long-term preventive effects of RXM, for 20 weeks young adult IL-10-deficient mice (4–5 weeks old) also were administered RXM orally (20 mg/kg per day).
Results: The short-term treatment-oriented administration of RXM reduced the degree of inflammatory change and lowered serum amyloid A in IL-10-deficient mice with severe colitis. Mononuclear cells from the lamina propria of RXM-treated large intestines showed lower production of IFN-γ than did those from diseased mice that were untreated. Long-term prevention-oriented administration of RXM suppressed the development of severe colitis and decreased production of IFN-γ and IL-12. In addition to its expected immunosuppressive effect, RXM treatment also decreased the level of Bacteroides vulgatus, a Gram-negative anaerobe.
Conclusions: The anti-inflammatory changes observed in IL-10-deficient mice resulted from the efficacy of RXM as an immunosuppressant as well as from its efficacy as an antibiotic. According to our findings, RXM would seem to have significant potential as a preventive and/or therapeutic agent for IBD.
(Inflamm Bowel Dis 2007)
REFERENCES
- 1 Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993; 75: 263–274.
- 2 Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996; 98: 1010–1020.
- 3 Sher A, Fiorentino D, Caspar P, Pearce E, Mosmann TR. Production of IL-10 by CD4+ T lymphocytes correlates with down-regulation of Th1 cytokine synthesis in helminth infection. J Immunol. 1991; 147: 2713–2716.
- 4 O'Garra A, Chang R, Go N, Hastings R, Haughton G, Howard M. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol. 1992; 22: 711–717.
- 5 Mosmann TR. Cytokine secretion patterns and cross-regulation of T cell subsets. Immunol Res. 1991; 10: 183–188.
- 6 Davidson NJ, Hudak SA, Lesley RE, Menon S, Leach MW, Rennick DM. IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol. 1998; 161: 3143–3149.
- 7 Davidson NJ, Leach MW, Fort MM, et al. T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J Exp Med. 1996; 184: 241–251.
- 8 Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998; 66: 5224–5231.
- 9 Kishi D, Takahashi I, Kai Y, et al. Alteration of V beta usage and cytokine production of CD4+ TCR beta beta homodimer T cells by elimination of Bacteroides vulgatus prevents colitis in TCR alpha-chain-deficient mice. J Immunol. 2000; 165: 5891–5899.
- 10 Madsen KL, Doyle JS, Tavernini MM, Jewell LD, Rennie RP, Fedorak RN. Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology. 2000; 118: 1094–1105.
- 11 O'Morain C. Elemental diets in the treatment of Crohn's disease. Porc Nurt Soc. 1979; 38: 403–408.
- 12 Ursing B, Kamme C. Metronidazole for Crohn's disease. Lancet. 1975; 1: 775–777.
- 13 Bousvaros A, Leichtner AM, Book L, et al. Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). Gastroenterology. 1996; 111: 237–243.
- 14 Sandborn WJ. A controlled trial of anti-tumor necrosis factor alpha antibody for Crohn's disease. Gastroenterology. 1997; 113: 1042–1043.
- 15 Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet. 1990; 336: 16–19.
- 16 Sandborn WJ, Tremaine WJ. Cyclosporine treatment of inflammatory bowel disease. Mayo Clin Proc. 1992; 67: 981–990.
- 17 Ito H, Hirotani T, Yamamoto M, Ogawa H, Kishimoto T. Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease. J Gastroenterol. 2002; 37(Suppl 14): 56–61.
- 18 van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology. 1995; 109: 129–135.
- 19 Agen C, Danesi R, Blandizzi C, et al. Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role. Agents Actions. 1993; 38: 85–90.
- 20 Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001; 429: 209–229.
- 21 Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med. 2003; 97: 844–850.
- 22 Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002; 360: 978–984.
- 23 Konno S, Adachi M, Asano K, Kawazoe T, Okamoto K, Takahashi T. Influences of roxithromycin on cell-mediated immune responses. Life Sci. 1992; 51: PL107–P112.
- 24 Mikamo H, Kawazoe K, Izumi K, Tamaya T. Effects of long-term administration of roxithromycin on neutrophil count and interleukin-8 level in endometrial cavity subjected to pyometra. Chemotherapy. 1997; 43: 148–152.
- 25 Nakamura H, Fujishima S, Inoue T, et al. Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection. Eur Respir J. 1999; 13: 1371–1379.
- 26 Shafran I, Kugler L, El-Zaatari FA, Naser SA, Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Dig Liver Dis. 2002; 34: 22–28.
- 27 Leiper K, Morris AI, Rhodes JM. Open label trial of oral clarithromycin in active Crohn's disease. Aliment Pharmacol Ther. 2000; 14: 801–806.
- 28 Gui GP, Thomas PR, Tizard ML, Lake J, Sanderson JD, Hermon-Taylor J. Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother. 1997; 39: 393–400.
- 29 Puri SK, Lassman HB. Roxithromycin: a pharmacokinetic review of a macrolide. J Antimicrob Chemother. 1987; 20(Suppl B): 89–100.
- 30
Arimori K,
Miyamoto S,
Fukuda K,
Nakamura C,
Nakano M.
Characteristic difference in gastrointestinal excretion of clarithromycin and roxithromycin.
Biopharm Drug Dispos.
1998;
19:
433–438.
10.1002/(SICI)1099-081X(199810)19:7<433::AID-BDD122>3.0.CO;2-Z CAS PubMed Web of Science® Google Scholar
- 31 Mombaerts P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell. 1993; 75: 274–282.
- 32 Fujihashi K, Taguchi T, Aicher WK, et al. Immunoregulatory functons for murine intraepithelial lymphocytes; gamma/delta T cell receptor-positive (TCR+) T cells abrogate orla tolerance, while alpha/beta TCR+ T cells provide B cell help. J Exp Med. 1992; 175: 695–707.
- 33 Takahashi I, Kiyono H, Hamada S. CD4+ T-cell population mediates development of inflammatory bowel disease in T-cell receptor a chain-deficient mice. Gastroenterology. 1997; 112: 1876–1886.
- 34 Ohta N, Hiroi T, Kweon MN, Kinoshita N, Jang MH, Mashimo T, Miyazaki J, Kiyono H. IL-15-dependent activation-induced cell death-resistant Th1 type CD8 alpha beta+NK1.1+ T cells for the development of small intestinal inflammation. J Immunol. 2002; 169: 460–468.
- 35 Kobayashi M, Kweon MN, Kuwata H, et al. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J Clin Invest. 2003; 111: 1297–1308.
- 36 Spencer DM, Veldman GM, Banerjee S, Willis J, Levine AD. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology. 2002; 122: 94–105.
- 37 Openshaw P, Murphy EE, Hosken NA, et al. Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J Exp Med. 1995; 182: 1357–1367.
- 38 Shah PM, Schafer V, Hubener T, Metz C, Stille W. Bactericidal activity of ofloxacin versus roxithromycin in the treatment of Streptococcus pneumoniae. Drugs. 1987; 34 Suppl 1: 9–13.
- 39 Amsden GW. Advanced-generation macrolides: tissue-directed antibiotics. Int J Antimicrob Agents 2001; 18(Suppl 1): S11–S15.
- 40 Fort M, Lesley R, Davidson N, et al. IL-4 exacerbates disease in a Th1 cell transfer model of colitis. J Immunol. 2001; 166: 2793–2800.
- 41 Wasowska B, Wieder KJ, Hancock WW, et al. Cytokine and alloantibody networks in long term cardiac allografts in rat recipients treated with rapamycin. J Immunol. 1996; 156: 395–404.
- 42 Morikawa K, Zhang J, Nonaka M, Morikawa S. Modulatory effect of macrolide antibiotics on the Th1- and Th2-type cytokine production. Int J Antimicrob Agents. 2002; 19: 53–59.
- 43 Asano K, Kamakazu K, Hisamitsu T, Suzaki H. Modulation of Th2 type cytokine production from human peripheral blood leukocytes by a macrolide antibiotic, roxithromycin, in vitro. Int Immunopharmacol. 2001; 1: 1913–1921.
- 44 Neurath MF, Fuss I, Kelsall B, Meyer zum Buschenfelde KH, Strober W. Effect of IL-12 and antibodies to IL-12 on established granulomatous colitis in mice. Ann N Y Acad Sci. 1996; 795: 368–370.
- 45 Adorini L, Gregori S, Magram J, Trembleau S. The role of IL-12 in the pathogenesis of Th1 cell-mediated autoimmune diseases. Ann N Y Acad Sci. 1996; 795: 208–215.
- 46 Magram J, Connaughton SE, Warrier RR, et al. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996; 4: 471–481.
- 47 Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995; 182: 1281–1290.
- 48 Bamba T, Matsuda H, Endo M, Fujiyama Y. The pathogenic role of Bacteroides vulgatus in patients with ulcerative colitis. J Gastroenterol. 1995; 30(Suppl 8): 45–47.
- 49 Onderdonk AB, Bronson R, Cisneros R. Comparison of Bacteroides vulgatus strains in the enhancement of experimental ulcerative colitis. Infect Immun. 1987; 55: 835–836.
- 50 Breeling JL, Onderdonk AB, Cisneros RL, Kasper DL. Bacteroides vulgatus outer membrane antigens associated with carrageenan-induced colitis in guinea pigs. Infect Immun. 1988; 56: 1754–1759.
- 51 Kullberg MC, Ward JM, Gorelick PL, et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect Immun. 1998; 66: 5157–5166.
- 52 Kullberg MC, Rothfuchs AG, Jankovic D, et al. Helicobacter hepaticus–induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun. 2001; 69: 4232–4241.
- 53 Dieleman LA, Arends A, Tonkonogy SL, et al. Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. Infect Immun. 2000; 68: 5107–5113.
- 54 Balish E, Warner T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol. 2002; 160: 2253–2257.
- 55 Madsen KL, Doyle JS, Jewell LD, Tavernini MM, Fedorak RN. Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology. 1999; 116: 1107–1114.
- 56 Pena JA, Rogers AB, Ge Z, et al. Probiotic Lactobacillus spp. diminish Helicobacter hepaticus–induced inflammatory bowel disease in interleukin-10-deficient mice. Infect Immun. 2005; 73: 912–920.
- 57 McCarthy J, O'Mahony L, O'Callaghan L, et al. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut. 2003; 52: 975–980.
- 58 Kamada N, Inoue N, Hisamatsu T, Okamoto S, Matsuoka K, Sato T, Chinen H, Hong KS, Yamada T, Suzuki Y, Suzuki T, Watanabe N, Tsuchimoto K, Hibi T. Nonpathogenic Escherichia coli strain Nissle1917 prevents murine acute and chronic colitis. Inflamm Bowel Dis. 2005; 11: 455–463.
- 59 Matsuda H, Fujiyama Y, Andoh A, Ushijima T, Kajinami T, Bamba T. Characterization of antibody responses against rectal mucosa-associated bacterial flora in patients with ulcerative colitis. J Gastroenterol Hepatol. 2000; 15: 61–68.
- 60 Hashimoto M, Kirikae F, Dohi T, Kusumoto S, Suda Y, Kirikae T. Structural elucidation of a capsular polysaccharide from a clinical isolate of Bacteroides vulgatus from a patient with Crohn's disease. Eur J Biochem. 2001; 268: 3139–3144.
- 61 Tamaoki J, Sakai N, Tagaya E, Konno K. Macrolide antibiotics protect against endotoxin-induced vascular leakage and neutrophil accumulation in rat trachea. Antimicrob Agents Chemother. 1994; 38: 1641–1643.
