Journal of Gastroenterology

, Volume 43, Issue 1, pp 1–17 | Cite as

Inflammatory bowel disease, past, present and future: lessons from animal models

  • Atsushi Mizoguchi
  • Emiko Mizoguchi
Review

Abstract

Accumulating data from animal models indicate that Inflammatory bowel disease (IBD) is mediated by a much more complicated mechanism than previously predicted. For example, the role of an individual molecule in the pathogenesis of IBD distinctly differs depending on several factors, including the fundamental mechanism of induction of the disease, the target cell type, the phase of disease, and the environment. Therefore, it has been difficult in the past to fully explain the complicated mechanism. Novel concepts have recently been proposed to further explain the complicated mechanism of IBD. In this review, we introduce past, current, and possible future concepts for IBD models regarding T helper (Th) 1, Th2, and Th17, antigen sampling and presentation, regulatory cell networks, NOD2, Toll-like receptors, bacteria/epithelia interaction, stem cells, autophagy, microRNAs, and glycoimmunology, and we also discuss the relevance of these new concepts, developed at the bench (in animal models), to the bedside.

Key words

antigen sampling autophagy IBD Breg mucin NOD2 Th17 TLRs 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Sands BE. Inflammatory bowel disease: past, present and future. J Gastroenterol 2007;42:16–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Kucharzik T, Maaser C, Lugering A, Kagnoff M, Mayer L, Targan S, et al. Recent understanding of IBD pathogenesis: implications for future therapies. Inflamm Bowel Dis 2006;12:1068–83.PubMedCrossRefGoogle Scholar
  3. 3.
    Xavier RJ, Podilsky DK. Unravelling the pathogenesis of Inflammatory bowel disease. Nature 2007;448:427–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Cho JH, Abraham C. Inflammatory bowel disease genetics: Nod2. Annu Rev Med 2007;58:401–16.PubMedCrossRefGoogle Scholar
  5. 5.
    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;75:274–82.PubMedCrossRefGoogle Scholar
  6. 6.
    Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993;75:263–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol 2002;20:495–549.PubMedCrossRefGoogle Scholar
  9. 9.
    Mizoguchi A, Mizoguchi E, Bhan AK. Immune networks in animal models of Inflammatory bowel disease. Inflamm Bowel Dis 2003;9:246–59.PubMedCrossRefGoogle Scholar
  10. 10.
    Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, Weaver CT. Experimental models of Inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev 2005;206:260–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Strober W, Fuss I, Mannon P. The fundamental basis of Inflammatory bowel disease. J Clin Invest 2007;117:514–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 1994;107:1643–52.PubMedGoogle Scholar
  13. 13.
    Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med 2002;8:567–73.PubMedCrossRefGoogle Scholar
  14. 14.
    Yen D, Cheun J, Scheerens H, Poulet F, McClanahan T, Mckenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 2006;116:1310–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 2006;25:309–18.PubMedCrossRefGoogle Scholar
  16. 16.
    Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006;203:2485–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 2006;203:2473–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 2007;132:2359–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Mizoguchi A, Ogawa A, Takedatsu H, Sugimoto K, Shimomura Y, Shirane K, et al. Dependence of intestinal granuloma formation on unique myeloid DC-like cells. J Clin Invest 2007;117:605–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association identifies IL23R as an Inflammatory bowel disease gene. Science 2006;314:1461–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, et al. IL-23 receptor (IL-23R) gene protects against pediatric Crohn’s disease. Inflamm Bowel Dis 2007;13:511–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Becker C, Dornhoff H, Neufert C, Fantini MC, Wirtz S, Huebner S, et al. IL-23 cross regulates IL-12 production in T cell-dependent experimental colitis. J Immunol 2006;177:2760–4.PubMedGoogle Scholar
  23. 23.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor â induces development of the Th17 lineage. Nature 2006;441:231–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFâ in the context of an Inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179–89.PubMedCrossRefGoogle Scholar
  26. 26.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORγt directs the differentiation program of proInflammatory IL-17+ T helper cells. Cell 2006;126:1121–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006;24:677–88.PubMedCrossRefGoogle Scholar
  28. 28.
    Steinman L. A brief history of Th17, the first major revision in the Th1/Th2 hypothesis of T cell-mediated tissue damage. Nat Med 2007;13:139–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal Th17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in Inflammatory bowel disease. Gut 2003;52:65–70.PubMedCrossRefGoogle Scholar
  31. 31.
    Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and-17 in active Inflammatory bowel disease. Scan J Gastroenterol 2003;38:180–5.CrossRefGoogle Scholar
  32. 32.
    Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006;12:382–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-wit D, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and Inflammatory disease. Nat Immunol 2007;8:247–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 2004;110:55–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Sugimoto K, Ogawa A, Shimomura Y, Nagahama K, Mizoguchi A, Bhan AK. Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation. Gastroenterology 2007;133:124–36.PubMedCrossRefGoogle Scholar
  36. 36.
    Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, et al. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med 2006;203:2715–25.PubMedCrossRefGoogle Scholar
  37. 37.
    Lohr J, Knoechel B, Wang JJ, Villarino AV, Abbas AK. Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J Exp Med 2006;203:2785–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007;204:1849–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity 2004;1:241–54.CrossRefGoogle Scholar
  40. 40.
    Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, et al. Interleukin-22, a member of the IL-10 subfamily, induces Inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 2005;129:969–84.PubMedCrossRefGoogle Scholar
  41. 41.
    Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-22 is increased in active Crohn’s disease and promotes proInflammatory gene expression and intestinal epithelial cell migration. Am J Physiol 2006;290:G827–38.Google Scholar
  42. 42.
    Wolk K, Witte E, Hoffmann U, Doecke W-D, Endesfelder S, Asadullah K, et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J Immunol 2007;178:5973–81.PubMedGoogle Scholar
  43. 43.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, et al. 2006. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006;203:2271–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a Th17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007;445:648–51.PubMedCrossRefGoogle Scholar
  45. 45.
    Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R. Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int Immunopharmacol 2004;4:679–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Dalwadi H, Wie B, Kronenberg M, Sutton CL, Braun J. The Crohn’s disease-associated bacterial protein I2 is a novel enteric T cell superantigen. Immunity 2001;15:149–58.PubMedCrossRefGoogle Scholar
  47. 47.
    Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 2004;113:1296–306.PubMedGoogle Scholar
  48. 48.
    MacDonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005;307:1920–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Kraehenbuhl JP, Neutral MR. Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 2000;16:301–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001;2:361–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 2005;307:254–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Yoshida M, Claypool SM, Wagner JS, Mizoguchi E, Mizoguchi A, Roopenian DC, et al. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 2004;20:769–83.PubMedCrossRefGoogle Scholar
  53. 53.
    Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, Claypool SM, et al. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 2006;116:2142–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Li H, Nowak-Wegrzyn A, Charlop-Powers Z, Shreffler W, Chehade M, Thomas S, et al. Transcytosis of IgE-antigen complexes by CD23a in human intestinal epithelial cells and its role in food allergy. Gastroenterology 2006;131:47–58.PubMedCrossRefGoogle Scholar
  55. 55.
    Kelsall BL, Leon F. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and Inflammatory bowel disease. Immunol Rev 2005;206:132–48.PubMedCrossRefGoogle Scholar
  56. 56.
    Rescigno M. CCR6(+) dendritic cells: the gut tactical-response unit. Immunity 2006;24:508–10.PubMedCrossRefGoogle Scholar
  57. 57.
    Iwasaki A. Mucosal dendritic cells. Annu Rev Immunol 2007;25:381–418.PubMedCrossRefGoogle Scholar
  58. 58.
    Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell 2001;106:255–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Gonzalez-Rey E, Delgado M. Therapeutic treatment of experimental colitis with regulatory dendritic cells generated with vasoactive intestinal peptide. Gastroenterology 2006;131:1799–811.PubMedCrossRefGoogle Scholar
  60. 60.
    Pedersen AE, Gad M, Kristensen NN, Haase C, Nielsen CH, Claesson MH. Tolerogenic dendritic cells pulsed with enterobacterial extract suppress development of colitis in the severe combined immunodeficiency transfer model. Immunology 2007;121:526–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Ordway D, Henau-Tamayo M, Orme IM, Gonzalez-Juarrero M. Foamy macrophages within lung granulomas of mice infected with Mycobacterium tuberculosis express molecules characteristic of dendritic cells and antiapoptotic markers of the TNF receptor-associated factor family. J Immunol 2005;175:3873–81.PubMedGoogle Scholar
  62. 62.
    Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organspecific autoimmune disease induced in mice by elimination of T cell subset. I evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 1985;161:72–87.PubMedCrossRefGoogle Scholar
  63. 63.
    Powrie F, Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J Exp Med 1990;172:1701–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Makita S, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, et al. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J Immunol 2007;178:4937–46.PubMedGoogle Scholar
  65. 65.
    Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 2006;212:256–71.PubMedCrossRefGoogle Scholar
  67. 67.
    Roncarolo MG, Battaglia M. Regulatory T cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007;7:585–98.PubMedCrossRefGoogle Scholar
  68. 68.
    Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007;8:457–62.PubMedCrossRefGoogle Scholar
  69. 69.
    Iweala O, Nagler CR. Immune privilege in the gut: the establishment and maintenance of non-responsiveness to dietary antigens and commensal flora. Immunol Rev 2006;213:82–100.PubMedCrossRefGoogle Scholar
  70. 70.
    Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000;1:475–82.PubMedCrossRefGoogle Scholar
  71. 71.
    Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal Inflammatory condition generates IL-10 producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002;16:219–30.PubMedCrossRefGoogle Scholar
  72. 72.
    Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002;3:944–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003;197:489–501.PubMedCrossRefGoogle Scholar
  74. 74.
    Burke F, Stagg AJ, Bedford PA, English N, Knight SC. IL-10-producing B220+CD11c-APC in mouse spleen. J Immunol 2004;173:2362–72.PubMedGoogle Scholar
  75. 75.
    Duddy ME, Alter A, Bar-Or A. Distinct profiles of human B cell effector cytokines: a role in immune regulation? J Immunol 2004;172:3422–7.PubMedGoogle Scholar
  76. 76.
    Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 2004;173:6346–56.PubMedGoogle Scholar
  77. 77.
    Wagner M, Poeck H, Jahrsdoerfer B, Rothenfusser S, Prell D, Bohle B, et al. IL-12p70-dependent Th1 induction by human B cells requires combined activation with CD40 ligand and CpG DNA. J Immunol 2004;172:954–63.PubMedGoogle Scholar
  78. 78.
    Gillan V, Lawrence RA, Devaney E. B cells play a regulatory role in mice infected with the L3 of Brugia Pahangi. Int Immunol 2005;17:373–82.PubMedCrossRefGoogle Scholar
  79. 79.
    Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, Mor F, Carmi P, Zanin-Zhorov A, et al. Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway. J Immunol 2005;175:3594–602.PubMedGoogle Scholar
  80. 80.
    Matsumura Y, Byrne SN, Nghiem DX, Miyahara Y, Ullrich SE. A role for Inflammatory mediators in the induction of immunoregulatory B cells. J Immunol 2006;177:4810–7.PubMedGoogle Scholar
  81. 81.
    Blenman KRM, Duan B, Xu ZW, Wan SG, Atkinson MA, Flotte TR, et al. IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest 2006;86:1136–48.PubMedGoogle Scholar
  82. 82.
    Inoue S, Leitner WW, Golding B, Scott D. Inhibitory effects of B cells on antitumor immunity. Cancer Res 2006;66:7741–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Kamanaka M, Kim ST, Wan YY, Sutterwala FS, Lara-Tejero M, Galan JE, et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 receptor knock in tiger mouse. Immunity 2006;25:941–52.PubMedCrossRefGoogle Scholar
  84. 84.
    Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF) a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989;170:827–37.PubMedCrossRefGoogle Scholar
  85. 85.
    Liu N, Ohnishi N, Ni L, Akira S, Bacon KB. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nat Immunol 2003;4:687–93.PubMedCrossRefGoogle Scholar
  86. 86.
    Rachmilewitz D, Karmeli F, Takabayashi K, Hayashi T, Leider-Trejo L, Lee J, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002;122:1428–41.PubMedCrossRefGoogle Scholar
  87. 87.
    Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, et al. Toll-like receptor 9 signaling mediates the anti-Inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 2004;126:520–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, Raz E. Toll like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 2005;115:695–702.PubMedGoogle Scholar
  89. 89.
    Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, et al. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor â2 deficient mice: IL-12 responsiveness is not required in the pathogenesis of Inflammatory demyelination in the central nervous system. J Immunol 2003;170:2153–60.PubMedGoogle Scholar
  90. 90.
    Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of T cell receptor α mutant mice. J Exp Med 1997;186:1749–56.PubMedCrossRefGoogle Scholar
  91. 91.
    Mizoguchi E, Mizoguchi A, Preffer FI, Bhan AK. Regulatory function role of mature B cells in a murine model of Inflammatory bowel disease. Int Immunol 2000;12:597–605.PubMedCrossRefGoogle Scholar
  92. 92.
    Gerth AJ, Lin L, Neurath MF, Glimcher LH, Peng SL. An innate cell-mediated, murine ulcerative colitis-like syndrome in the absence of nuclear factor of activated T cells. Gastroenterology 2004;126:1115–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Hokama A, Mizoguchi E, Sugimoto K, Shimomura Y, Tanaka Y, Yoshida M, et al. Induced reactivity of intestinal CD4+ T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity 2004;20:681–93.PubMedCrossRefGoogle Scholar
  94. 94.
    Wei B, Velazquez P, Turovskaya O, Spricher K, Aranda R, Kronenberg M, et al. Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets. Proc Natl Acad Sci U S A 2005;102:2010–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol 2006;176:705–10.PubMedGoogle Scholar
  96. 96.
    Ostanin DV, Pavlick KP, Bharwani S, D’souza D, Furr KL, Brown CM, et al. T cell-induced inflammation of the small and large intestine in immuno-deficient mice. Am J Physiol 2006;290:G109–19.Google Scholar
  97. 97.
    McGeachy MJ, Stephens LA, Anderton SM. Natural recovery and protection from autoimmune encephalomyelitis: contribu tion of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 2005;175:3025–32.PubMedGoogle Scholar
  98. 98.
    Milani M, Ostlie N, Wu H, Wang W, Conti-Fine BM. CD4+ T and B cells cooperate in the immunoregulation of experimental autoimmune myasthenia gravis. J Neuroimmunol 2006;179:152–62.PubMedCrossRefGoogle Scholar
  99. 99.
    Ashour HM, Niederkorn JY. Peripheral tolerance via the anterior chamber of the eye: role of B cells in MHC class I and II antigen presentation. J Immunol 2006;176:5950–7.PubMedGoogle Scholar
  100. 100.
    Olson TS, Bamias G, Naganuma M, Rivera-Nieves J, Burcin TL, Ross W, et al. Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn’s disease. J Clin Invest 2004;114:389–98.PubMedGoogle Scholar
  101. 101.
    Dohi T, Fujihashi K, Koga T, Shirai Y, Kawamura YI, Ejima C, et al. T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice. Gastroenterology 2003;124:672–82.PubMedCrossRefGoogle Scholar
  102. 102.
    Kawamura T, Kanai T, Dohi T, Uraushihara K, Totsuka T, Iiyama R, et al. Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. J Immunol 2004;172:6388–97.PubMedGoogle Scholar
  103. 103.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599–603.PubMedCrossRefGoogle Scholar
  104. 104.
    Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411:603–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Inohara, Chamaillard, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and Inflammatory disease. Annu Rev Biochem 2005;74:355–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007;369:1627–40.PubMedCrossRefGoogle Scholar
  107. 107.
    Pauleau AL, Murray PJ. Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol 2003;23:7531–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731–4.PubMedCrossRefGoogle Scholar
  109. 109.
    Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, et al. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science 2005;307:734–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 2006;313:1126–30.PubMedCrossRefGoogle Scholar
  111. 111.
    Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004;5:800–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Watanabe T, Kitani A, Murray PJ, Wakatsuki Y, Fuss IJ, Strober W. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 2006;25:473–85.PubMedCrossRefGoogle Scholar
  113. 113.
    Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker HC, Podolsky DK. GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of antibacterial function in intestinal epithelial cells. J Biol Chem 2005;280:19021–6.PubMedCrossRefGoogle Scholar
  114. 114.
    Chen CM, Gong Y, Zhang M, Chen JJ. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem 2004;279:25876–82.PubMedCrossRefGoogle Scholar
  115. 115.
    McDonald C, Chen FF, Ollendorff V, Ogura Y, Marchetto S, Lecine P, et al. A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling. J Biol Chem 2005;280:40301–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Yamamoto-Frusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK. Centaurin beta 1 down-regulates nucleotidebinding oligomerization domains 1 and 2 dependent NF-kappaB activation. J Biol Chem 2006;281:36060–70.CrossRefGoogle Scholar
  117. 117.
    Hsu YM, Zhang Y, You Y, Wang D, Li H, Duramad O, et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 2007;8:198–205.PubMedCrossRefGoogle Scholar
  118. 118.
    Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 2002;123:86–91.PubMedCrossRefGoogle Scholar
  119. 119.
    Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A. Association analysis of genetic variants in IL-23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet 2007;52:575–83.PubMedCrossRefGoogle Scholar
  120. 120.
    Medzhitov R, Preston-Hurlburt P, Janeway Jr CA. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 1997;388:394–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J Immunol 1999;162:3749–52.PubMedGoogle Scholar
  122. 122.
    Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335–76.PubMedCrossRefGoogle Scholar
  123. 123.
    Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004;5987–95.PubMedCrossRefGoogle Scholar
  124. 124.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;24:783–801.CrossRefGoogle Scholar
  125. 125.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229–41.PubMedCrossRefGoogle Scholar
  126. 126.
    Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol 2005;288:G1055–65.Google Scholar
  127. 127.
    Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol 2005;40:16–23.PubMedCrossRefGoogle Scholar
  128. 128.
    Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 2007;132:1359–74.PubMedCrossRefGoogle Scholar
  129. 129.
    Kitajima S, Morimoto M, Sagara E, Shimizu C, Ikeda Y. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp Anim 2001;50:387–95.PubMedCrossRefGoogle Scholar
  130. 130.
    Fort MM, Mozaffarian A, Stover AG, Correia Jda S, Johnson DA, Crane RT, et al. A systemic TLR4 antagonist has anti-inflammatory effects in two murine models of Inflammatory bowel disease. J Immunol 2005;174:6416–23.PubMedGoogle Scholar
  131. 131.
    Grabig A, Paclik D, Guzy C, Dankof A, Baumgart DC, Erckenbrecht J, et al. Infect Immun 2006;74:4075–82.PubMedCrossRefGoogle Scholar
  132. 132.
    Kabashima K, Saji T, Murata T, Nagamachi M, Matsuoka T, Segi E, et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest 2002;109:883–93.PubMedCrossRefGoogle Scholar
  133. 133.
    Lin F, Spencer D, Hatala DA, Levine AD, Medof ME. Decayaccelerating factor deficiency increases susceptibility to dextran sulfate sodium-induced colitis: role for complement in Inflammatory bowel disease. J Immunol 2004;172:3836–41.PubMedGoogle Scholar
  134. 134.
    Matsuura M, Okazaki K, Nishio A, Nakase H, Tamaki H, Uchida K, et al. Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis. Gastroenterology 2005;128:975–86.PubMedCrossRefGoogle Scholar
  135. 135.
    Mizoguchi E, Xavier RJ, Reinecker H-C, Uchino H, Bhan AK, Podolsky DK, et al. Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology 2003;125:148–61.PubMedCrossRefGoogle Scholar
  136. 136.
    Mizoguchi E. Chitinase 3-like 1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology 2006;130:398–411.PubMedCrossRefGoogle Scholar
  137. 137.
    Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048–53.PubMedCrossRefGoogle Scholar
  138. 138.
    Rakoff-Nahoum S, Hao L, Medzhitov R. Role of toll-like receptors in spontaneous commensal dependent colitis. Immunity 2006;25:319–29.PubMedCrossRefGoogle Scholar
  139. 139.
    Sanders CJ, Yu Y, Moore DA, Williams IR, Gewirtz AT. Humoral immune response to flagellin requires T cells and activation of innate immunity. J Immunol 2006;177:2810–8.PubMedGoogle Scholar
  140. 140.
    Gewirtz AT, Vijay-Kumar M, Brant SR, Duerr RH, Nicolae DL, Cho JH. Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn’s disease. Am J Physiol Gastrointest Liver Physiol 2006;290:G1157–63.PubMedCrossRefGoogle Scholar
  141. 141.
    Targan SR, Landers CJ, Yang H, Lodes MJ, Cong Y, Papadakis KA, et al. Antibodies to Cbir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology 2005;128:2020–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Papadakis KA, Yang H, Ippoliti A, Mei L, Elson CO, Hershberg RM, et al. Anti-flagellin (CBir1) phenotypic and genetic Crohn’s disease associations. Inflamm Bowel Dis 2007;13:524–30.PubMedCrossRefGoogle Scholar
  143. 143.
    Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL. Bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proInflammatory gene expression. J Immunol 2001;167:1882–5.PubMedGoogle Scholar
  144. 144.
    Rhee SH, Im E, Riegler M, Kokkotou E, O’brien M, Pothoulakis C. Pathophysiological role of toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc Natl Acad Sci USA 2005;102:13610–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995;374:546–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–5.PubMedCrossRefGoogle Scholar
  147. 147.
    Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signaling in intestinal epithelial cells. Nat Cell Biol 2006;8:1327–36.PubMedCrossRefGoogle Scholar
  148. 148.
    Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006;5:471–84.PubMedCrossRefGoogle Scholar
  149. 149.
    Rachmilewitz D, Karmeli F, Shteingart S, Lee J, Takanayashi K, Raz E. Immunostimulatory oligonucleotides inhibit colonic proinflammatory cytokine production in ulcerative colitis. Inflamm Bowel Dis 2006;12:339–45.PubMedCrossRefGoogle Scholar
  150. 150.
    Obermeier F, Straugh UG, Dunger N, Grunwald N, Rath HC, Herfarth H, et al. In vivo CpG DNA/toll-like receptor 9 interaction induces regulatory properties in CD4+CD62L+ T cells which prevent intestinal inflammation in the SCID transfer model of colitis. Gut 2005;54:1428–36.PubMedCrossRefGoogle Scholar
  151. 151.
    Obermeier F, Dunger N, Deml L, Herfarth H, Scholmeric J, Falk W. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol 2002;32:2084–92.PubMedCrossRefGoogle Scholar
  152. 152.
    Obermeier F, Dunger N, Strauch UG, Hofmann C, Bleich A, Grunwald N, et al. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 2005;129:913–27.PubMedCrossRefGoogle Scholar
  153. 153.
    Kuwata H, Matsumoto M, Atarashi K, Morishita H, Hirotani T, Koga R, et al. IêBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Immunity 2006;24:41–51.PubMedCrossRefGoogle Scholar
  154. 154.
    Vijay-Kumar M, Wu H, Aitken J, Kolachala VL, Neish AS, Sitaraman SV, et al. Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 2007;13:856–64.PubMedCrossRefGoogle Scholar
  155. 155.
    Hooper LV, Gordon JI. Commensal host-bacterial relationship in the gut. Science 2001;292:1115–8.PubMedCrossRefGoogle Scholar
  156. 156.
    Sartor RB. Therapeutic manipulation of the enteric microflora in Inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 2004;126:1620–33.PubMedCrossRefGoogle Scholar
  157. 157.
    Sonnenburg JL, Xu J, Leip DD, Chen CH, Westover BP, Weatherford J, et al. Glycan foraging in vivo by an intestineadapted bacterial symbiont. Science 2005;307:1955–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunoregulatory molecules of symbiotic bacteria directs maturation of the host immune system. Cell 2005;122:107–18.PubMedCrossRefGoogle Scholar
  159. 159.
    Barnich N, Cavalho FA, Glasser AL, Darcha C, Jantscheff P, Allez M, et al. CEACAM6 acts as a receptor for adherentinvasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest 2007;117:1566–74.PubMedCrossRefGoogle Scholar
  160. 160.
    Karrasch T, Kim J-S, Muhlbauer M, Magness ST, Jobin C. Gnotobiotic IL-10−/−;NF-κBEGFP mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis. J Immunol 2007;178:6522–32.PubMedGoogle Scholar
  161. 161.
    Dahan S, Roth-Walter F, Arnaboldi P, Agarwal S, Mayer L. Epithelia: lymphocyte interactions in the gut. Immunol Rev 2007;215:243–53.PubMedCrossRefGoogle Scholar
  162. 162.
    Shirazi T, Longman RJ, Corfield AP, Probert CS. Mucins and inflammatory bowel disease. Postgrad Med J 2000;76:473–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Rhodes JM. Unifying hypothesis for inflammatory bowel disease and associated colon cancer: sticking the pieces together with sugar. Lancet 1996;347:40–4.PubMedCrossRefGoogle Scholar
  164. 164.
    An G, Wei B, Xia B, McDaniel JM, Ju T, Cummings RD, et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 2007;204:1417–29.PubMedCrossRefGoogle Scholar
  165. 165.
    Van der Sluis M, De Koning BAE, De Bruijn ACJM, Velcich A, Meijerink JPP, Van Goudoever JB, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006;131:117–29.PubMedCrossRefGoogle Scholar
  166. 166.
    Ho SB, Dvorak LA, Moor RE, Jacobson AC, Frey MR, Corredor J, et al. Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing. Gastroenterology 2006;131:1501–17PubMedCrossRefGoogle Scholar
  167. 167.
    McAuley JL, Linden SK, Png CW, King RM, Pennington HL, Gendler SJ, et al. Muc1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest 2007;117:2313–24.PubMedCrossRefGoogle Scholar
  168. 168.
    Beatty PL, Plevy SE, Sepulveda AR, Finn OJ. Transgenic expression of human MUC1 in IL-10−/− mice accelerates inflammatory bowel disease and progression to colon cancer. J Immunol 2007;179:735–9.PubMedGoogle Scholar
  169. 169.
    Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defence of intestinal mucosa in mice lacking intestinal trefoil factor. Science 1996;274:262–5.PubMedCrossRefGoogle Scholar
  170. 170.
    Itoh H, Beck PL, Inoue N, Xavier R, Podolsky DK. A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells. J Clin Invest 1999;104:1539–47.PubMedCrossRefGoogle Scholar
  171. 171.
    McVay LD, Keilbaugh SA, Wong TM, Kierstein S, Shin ME, Lehrke M, et al. Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis. J Clin Invest 2006;116:2914–23.PubMedCrossRefGoogle Scholar
  172. 172.
    Hogan SP, Seidu L, Blanchard C, Groschwitz K, Mishra A, Karow ML, et al. Resistin-like molecule β regulates innate colonic function: barrier integrity and inflammation susceptibility. J Allergy Clin Immunol 2006;118:257–68.PubMedCrossRefGoogle Scholar
  173. 173.
    Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ, et al. Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation. Gastroenterology 2002;122:134–44.PubMedCrossRefGoogle Scholar
  174. 174.
    Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG. MyD88-mediated signals induce the bacterial lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J Exp Med 2007;204:1891–900.PubMedCrossRefGoogle Scholar
  175. 175.
    Allez M, Tieng V, Nakazawa A, Treton X, Pacault V, Dulphy N, et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology 2007;132:2346–58.PubMedCrossRefGoogle Scholar
  176. 176.
    He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 2007;26:812–26.PubMedCrossRefGoogle Scholar
  177. 177.
    Xu W, He B, Chiu A, Chadburn A, Shan M, Buldys M, et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat Immunol 2007;8:294–303.PubMedCrossRefGoogle Scholar
  178. 178.
    Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 2005;6:507–14.PubMedCrossRefGoogle Scholar
  179. 179.
    Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med 2000;6:583–8.PubMedCrossRefGoogle Scholar
  180. 180.
    Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 2002;8:1089–97.PubMedCrossRefGoogle Scholar
  181. 181.
    Neurath MF, Pettersson S, Meyer zum Buschenfelde KH, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 1996;2:998–1004.PubMedCrossRefGoogle Scholar
  182. 182.
    Shibata W, Maeda S, Hikiba Y, Yanai A, Ohmae T, Sakamoto K, et al. The IκB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. J Immunol 2007;179:2681–5.PubMedGoogle Scholar
  183. 183.
    Nenci A, Becker C, Wullaret A, Gareus R, van Loo G, Dansen S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007;446:557–61.PubMedCrossRefGoogle Scholar
  184. 184.
    Plevy S. A STAT need for human immunologic studies to understand inflammatory bowel disease. Am J Gastroenterol 2005;100:73–4.PubMedCrossRefGoogle Scholar
  185. 185.
    Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 2002;8:1011–7.PubMedCrossRefGoogle Scholar
  186. 186.
    Suzuki K, Oida T, Hamada H, Hitotsumatsu O, Watanabe M, Hibi T, et al. Gut cryptopatches: direct evidence of extrathymic anatomical sites for intestinal T lymphopoiesis. Immunity 2000;13:691–702.PubMedCrossRefGoogle Scholar
  187. 187.
    Chinen H, Matsuoka K, Sato T, Kamada N, Okamoto S, Hisamatsu T, et al. Lamina propria c-kit+ immature precursors reside in human adult intestine and differentiate into natural killer cells. Gastroenterology 2007;133:559–73.PubMedCrossRefGoogle Scholar
  188. 188.
    Khalil PN, Weiler V, Nelson PJ, Khalil MN, Moosmann S, Mutschler WE, et al. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 2007;132:944–54.PubMedCrossRefGoogle Scholar
  189. 189.
    Brittan M, Chance V, Elia G, Poulsom R, Alison MR, MacDonald TT, et al. A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology 2005;128:1984–95.PubMedCrossRefGoogle Scholar
  190. 190.
    Yoshimori T. Autophagy: paying Charon’s toll. Cell 2007;128:833–6.PubMedCrossRefGoogle Scholar
  191. 191.
    Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604.PubMedCrossRefGoogle Scholar
  192. 192.
    Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology 2007;132:1665–71.PubMedCrossRefGoogle Scholar
  193. 193.
    Xu Y, Jagannath C, Liu X-D, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 2007;27:135–44.PubMedCrossRefGoogle Scholar
  194. 194.
    Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 2007;128:931–46.PubMedCrossRefGoogle Scholar
  195. 195.
    Schmid D, Pypaert M, Munz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 2007;26:79–92.PubMedCrossRefGoogle Scholar
  196. 196.
    Schimid D, Munz C. Innate and adaptive immunity through autophagy. Immunity 2007;27:11–21.CrossRefGoogle Scholar
  197. 197.
    Steinhoff U, Brinkmann V, Klemm U, Aichele P, Seiler P, Brandt U, et al. Autoimmune intestinal pathology induced by hsp60 specific CD8 T cells. Immunity 1999;11:349–57.PubMedCrossRefGoogle Scholar
  198. 198.
    Mizoguchi A, Mizoguchi E, Saubermann LJ, Higaki K, Blumberg RS, Bhan AK. Limited CD4 T-cell diversity associated with colitis in T-cell receptor α mutant mice requires a T helper 2 environment. Gastroenterology 2000;119:983–95.PubMedCrossRefGoogle Scholar
  199. 199.
    Bamias G, Okazawa A, Rivera-Nieves J, Arseneau KO, De La Rue SA, Pizarro TT, et al. Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis. J Immunol 2007;178:1809–18.PubMedGoogle Scholar
  200. 200.
    Taganov KD, Boldin MP, Baltimore D. MicroRNAs and immunity: tiny players in a big field. Immunity 2007;26:133–7.PubMedCrossRefGoogle Scholar
  201. 201.
    Thai T-H, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science 2007;316:604–7.PubMedCrossRefGoogle Scholar
  202. 202.
    Continho LL, Matukumalli LK, Sonstegard TS, Van Tassell CP, Gasbarre LC, Capuco AV, et al. Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues. Physiol Genomics 2007;29:35–43.Google Scholar
  203. 203.
    Lowe JB. Glycosylation, immunity, and autoimmunity. Cell 2001;104:809–12.PubMedCrossRefGoogle Scholar
  204. 204.
    Baum LG. Developing a taste for sweets. Immunity 2002;16:5–8.PubMedCrossRefGoogle Scholar
  205. 205.
    Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol 2007;7:255–66.PubMedCrossRefGoogle Scholar
  206. 206.
    Van Vliet SJ, Gringhuis SI, Geijtenbeek TBH, van Kooyk Y. Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45. Nat Immunol 2006;7:1200–8.PubMedCrossRefGoogle Scholar
  207. 207.
    Green RS, Stone EL, Tennon M, Lehtonen E, Farquhar MG, Marth JD. Mammalian N-glycan branching protects against innate immune self-recognition and inflammation in autoimmune disease pathogenesis. Immunity 2007;27:1–13CrossRefGoogle Scholar
  208. 208.
    Uchimura K, Rosen SD. Sulfated l-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol 2006;27:559–65.PubMedCrossRefGoogle Scholar
  209. 209.
    Gringhuis SI, den Dunnen J, Litjens M, van her Hof B, van Kooyk Y, Geijtenbeek TBH. C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB. Immunity 2007;26:605–16.PubMedCrossRefGoogle Scholar
  210. 210.
    Cunningham AL, Harman AN, Donaghy H. DC-SIGN “AIDS” HIV immune evasion and infection. Nat Immunol 2007;8:556–8.PubMedCrossRefGoogle Scholar
  211. 211.
    Perillo NJ, Pace KE, Seihamer JJ, Baum LG. Apoptosis of T cells mediated by galectin-1. Nature 1995;378:736–9.PubMedCrossRefGoogle Scholar
  212. 212.
    Toscano MA, Bianco GA, Iiarregui JA, Croci DO, Correale J, Hernandez JD, et al. Differential glycosylation of Th1, Th2, and Th17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 2007;8:825–34.PubMedCrossRefGoogle Scholar
  213. 213.
    Santucci L, Fiorucci S, Rubinstein N, Mencarelli A, Palazzetti B, Federici B, et al. Galectin-1 suppresses experimental colitis in mice. Gastroenterology 2003;124:1381–94.PubMedCrossRefGoogle Scholar
  214. 214.
    Ideo H, Seko A, Ohkura T, Matta KL, Yamashita K. High affinity binding of recombinant human galectin-4 to SO(3)(−)->3Galbeta1->3GalNAc pyranoside. Glycobiology 2002;12:199–208.PubMedCrossRefGoogle Scholar
  215. 215.
    Mizoguchi E, Mizoguchi A. Is the sugar always sweet in intestinal inflammation? Immunol Res 2007;37:47–60PubMedCrossRefGoogle Scholar
  216. 216.
    Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Appendix lymphoid follicle plays an important role for development of inflammatory bowel disease in TCR-α mutant mice. J Exp Med 1996;184:707–15.PubMedCrossRefGoogle Scholar
  217. 217.
    Hegazi RAF, Rao KN, Mayle A, Sepulveda AR, Otterbein LE, Plevy SE. Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 2005;202:1703–13.PubMedCrossRefGoogle Scholar
  218. 218.
    Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157–60.PubMedCrossRefGoogle Scholar
  219. 219.
    Coombes JL, Siddiqui KRR, Arancibia-Carcamo CV, Hall J, Sun C-M, Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGFβ-and retinoic acid-dependent mechanism. J Exp Med 2007;204:1757–64.PubMedCrossRefGoogle Scholar
  220. 220.
    Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. AA-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007;2004:1765–74.CrossRefGoogle Scholar
  221. 221.
    Sun C-M, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J Exp Med 2007;204:1775–85.PubMedCrossRefGoogle Scholar
  222. 222.
    Sugimoto K, Hanai H, Tozawa K, Aoshi T, Uchijima M, Nagata T, et al. Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice. Gastroenterology 2002;123:1912–22.PubMedCrossRefGoogle Scholar
  223. 223.
    Arita M, Yoshida M, Hong S, Tjonahen E, Glickman JN, Petasis NA, et al. Resolvin E1, an endogenous lipid mediator derived from omega 3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci USA 2005;102:7671–6.PubMedCrossRefGoogle Scholar
  224. 224.
    Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, et al. Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc Natl Acad Sci USA 2006;103:11276–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Atsushi Mizoguchi
    • 1
    • 2
  • Emiko Mizoguchi
    • 2
    • 3
  1. 1.Department of PathologyExperimental PathologyBostonUSA
  2. 2.Center for the Study of Inflammatory Bowel DiseaseMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Department of MedicineMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations