• 1
    Strober, W., Fuss, I. and Mannon, P., The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 2007. 117: 514521.
  • 2
    Xavier, R. J. and Podolsky, D. K., Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007. 448: 427434.
  • 3
    Akira, S., Uematsu, S. and Takeuchi, O., Pathogen recognition and innate immunity. Cell 2006. 124: 783801.
  • 4
    Fritz, J. H., Ferrero, R. L., Philpott, D. J. and Girardin, S. E., Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 2006. 7: 12501257.
  • 5
    Hugot, J. P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J. P., Belaiche, J., Almer, S. et al., Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001. 411: 599603.
  • 6
    Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H. et al., A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001. 411: 603606.
  • 7
    Cho, J. H. and Abraham, C., Inflammatory bowel disease genetics: Nod2. Annu. Rev. Med. 2007. 58: 401416.
  • 8
    Strober, W., Murray, P. J., Kitani, A. and Watanabe, T., Signalling pathways and molecular interactions of NOD1 and NOD2. Nat. Rev. Immunol. 2006. 6: 920.
  • 9
    Torok, H. P., Glas, J., Tonenchi, L., Bruennler, G., Folwaczny, M. and Folwaczny, C., Crohn's disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology 2004. 127: 365366.
  • 10
    De Jager, P. L., Franchimont, D., Waliszewska, A., Bitton, A., Cohen, A., Langelier, D., Belaiche, J. et al., The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun. 2007. 8: 387397.
  • 11
    Pierik, M., Joossens, S., Van Steen, K., Van Schuerbeek, N., Vlietinck, R., Rutgeerts, P. and Vermeire, S., Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm. Bowel Dis. 2006. 12: 18.
  • 12
    Cario, E., Therapeutic impact of toll-like receptors on inflammatory bowel diseases: a multiple-edged sword. Inflamm. Bowel Dis. 2008. 14: 411421.
  • 13
    Fukata, M., Michelsen, K. S., Eri, R., Thomas, L. S., Hu, B., Lukasek, K., Nast, C. C. 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. Gastrointest. Liver Physiol. 2005. 288: G1055G1065.
  • 14
    Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. and Medzhitov, R., Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004. 118: 229241.
  • 15
    Cario, E., Gerken, G. and Podolsky, D. K., Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 2007. 132: 13591374.
  • 16
    Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M. et al., Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007. 446: 557561.
  • 17
    Zaph, C., Troy, A. E., Taylor, B. C., Berman-Booty, L. D., Guild, K. J., Du, Y., Yost, E. A. et al., Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 2007. 446: 552556.
  • 18
    Rakoff-Nahoum, S., Hao, L. and Medzhitov, R., Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 2006. 25: 319329.
  • 19
    Obermeier, F., Dunger, N., Deml, L., Herfarth, H., Scholmerich, J. and Falk, W., CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur. J. Immunol. 2002. 32: 20842092.
  • 20
    Rhee, S. H., Im, E., Riegler, M., Kokkotou, E., O'Brien, M. and Pothoulakis, C., Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc. Natl. Acad. Sci. USA 2005. 102: 1361013615.
  • 21
    Fort, M. M., Mozaffarian, A., Stover, A. G., Correia Jda, S., Johnson, D. A., Crane, R. T., Ulevitch, R. J. et al., A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 2005. 174: 64166423.
  • 22
    Kabelitz, D., Expression and function of Toll-like receptors in T lymphocytes. Curr. Opin. Immunol. 2007. 19: 3945.
  • 23
    Caron, G., Duluc, D., Fremaux, I., Jeannin, P., David, C., Gascan, H. and Delneste, Y., Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J. Immunol. 2005. 175: 15511557.
  • 24
    Gelman, A. E., LaRosa, D. F., Zhang, J., Walsh, P. T., Choi, Y., Sunyer, J. O. and Turka, L. A., The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity 2006. 25: 783793.
  • 25
    Komai-Koma, M., Jones, L., Ogg, G. S., Xu, D. and Liew, F. Y., TLR2 is expressed on activated T cells as a costimulatory receptor. Proc. Natl. Acad. Sci. USA 2004. 101: 30293034.
  • 26
    Sutmuller, R. P., Morgan, M. E., Netea, M. G., Grauer, O. and Adema, G. J., Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol. 2006. 27: 387393.
  • 27
    Crellin, N. K., Garcia, R. V., Hadisfar, O., Allan, S. E., Steiner, T. S. and Levings, M. K., Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J. Immunol. 2005. 175: 80518059.
  • 28
    Liu, H., Komai-Koma, M., Xu, D. and Liew, F. Y., Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc. Natl. Acad. Sci. USA 2006. 103: 70487053.
  • 29
    Peng, G., Guo, Z., Kiniwa, Y., Voo, K. S., Peng, W., Fu, T., Wang, D. Y. et al., Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005. 309: 13801384.
  • 30
    Sutmuller, R. P., den Brok, M. H., Kramer, M., Bennink, E. J., Toonen, L. W., Kullberg, B. J., Joosten, L. A. et al., Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 2006. 116: 485494.
  • 31
    Zanin-Zhorov, A., Cahalon, L., Tal, G., Margalit, R., Lider, O. and Cohen, I. R., Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J. Clin. Invest. 2006. 116: 20222032.
  • 32
    Cario, E., Gerken, G. and Podolsky, D. K., Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 2004. 127: 224238.
  • 33
    Netea, M. G., Sutmuller, R., Hermann, C., Van der Graaf, C. A., Van der Meer, J. W., van Krieken, J. H., Hartung, T. et al., Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol. 2004. 172: 37123718.
  • 34
    Imanishi, T., Hara, H., Suzuki, S., Suzuki, N., Akira, S. and Saito, T., Cutting edge: TLR2 directly triggers Th1 effector functions. J. Immunol. 2007. 178: 67156719.
  • 35
    Watanabe, T., Kitani, A., Murray, P. J. and Strober, W., NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat. Immunol. 2004. 5: 800808.
  • 36
    Watanabe, T., Kitani, A., Murray, P. J., Wakatsuki, Y., Fuss, I. J. and Strober, W., Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 2006. 25: 473485.
  • 37
    Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B. and Coffman, R. L., Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 1993. 5: 14611471.
  • 38
    Hue, S., Ahern, P., Buonocore, S., Kullberg, M. C., Cua, D. J., McKenzie, B. S., Powrie, F. and Maloy, K. J., Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 2006. 203: 24732483.
  • 39
    Maloy, K. J., Salaun, L., Cahill, R., Dougan, G., Saunders, N. J. and Powrie, F., CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 2003. 197: 111119.
  • 40
    Kullberg, M. C., Jankovic, D., Feng, C. G., Hue, S., Gorelick, P. L., McKenzie, B. S., Cua, D. J. et al., IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 2006. 203: 24852494.
  • 41
    Mandell, L., Moran, A. P., Cocchiarella, A., Houghton, J., Taylor, N., Fox, J. G., Wang, T. C. and Kurt-Jones, E. A., Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. Infect. Immun. 2004. 72: 64466454.
  • 42
    Smith, M. F., Jr., Mitchell, A., Li, G., Ding, S., Fitzmaurice, A. M., Ryan, K., Crowe, S. and Goldberg, J. B., Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J. Biol. Chem. 2003. 278: 3255232560.
  • 43
    Read, S., Malmstrom, V. and Powrie, F., Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 2000. 192: 295302.
  • 44
    Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y., Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 2003. 4: 330336.
  • 45
    Ge, Z., White, D. A., Whary, M. T. and Fox, J. G., Fluorogenic PCR-based quantitative detection of a murine pathogen, Helicobacter hepaticus. J. Clin. Microbiol. 2001. 39: 25982602.
  • 46
    Frolova, L., Drastich, P., Rossmann, P., Klimesova, K. and Tlaskalova-Hogenova, H., Expression of toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. J. Histochem. Cytochem. 2008. 56: 267274.
  • 47
    Watanabe, T., Asano, N., Murray, P. J., Ozato, K., Tailor, P., Fuss, I. J., Kitani, A. and Strober, W., Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J. Clin. Invest. 2008. 118: 545559.
  • 48
    Karrasch, T., Kim, J. S., Muhlbauer, M., Magness, S. T. and Jobin, C., Gnotobiotic IL-10−/−;NF-kappa B(EGFP) mice reveal the critical role of TLR/NF-kappa B signaling in commensal bacteria-induced colitis. J. Immunol. 2007. 178: 65226532.
  • 49
    Sterzenbach, T., Lee, S. K., Brenneke, B., von Goetz, F., Schauer, D. B., Fox, J. G., Suerbaum, S. and Josenhans, C., Inhibitory effect of enterohepatic Helicobacter hepaticus on innate immune responses of mouse intestinal epithelial cells. Infect. Immun. 2007. 75: 27172728.
  • 50
    Andersen-Nissen, E., Smith, K. D., Strobe, K. L., Barrett, S. L., Cookson, B. T., Logan, S. M. and Aderem, A., Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl. Acad. Sci. USA 2005. 102: 92479252.
  • 51
    Rachmilewitz, D., Karmeli, F., Takabayashi, K., Hayashi, T., Leider-Trejo, L., Lee, J., Leoni, L. M. and Raz, E., Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002. 122: 14281441.
  • 52
    Rachmilewitz, D., Katakura, K., Karmeli, F., Hayashi, T., Reinus, C., Rudensky, B., Akira, S. et al., Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 2004. 126: 520528.
  • 53
    Obermeier, F., Strauch, U. G., Dunger, N., Grunwald, N., Rath, H. C., Herfarth, H., Scholmerich, J. and Falk, W., 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: 14281436.
  • 54
    Obermeier, F., Dunger, N., Strauch, U. G., Hofmann, C., Bleich, A., Grunwald, N., Hedrich, H. J. et al., CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 2005. 129: 913927.
  • 55
    Viala, J., Chaput, C., Boneca, I. G., Cardona, A., Girardin, S. E., Moran, A. P., Athman, R. et al., Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol. 2004. 5: 11661174.
  • 56
    El-Omar, E. M., Carrington, M., Chow, W. H., McColl, K. E., Bream, J. H., Young, H. A., Herrera, J. et al., Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000. 404: 398402.
  • 57
    Aranda, R., Sydora, B. C., McAllister, P. L., Binder, S. W., Yang, H. Y., Targan, S. R. and Kronenberg, M., Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. J. Immunol. 1997. 158: 34643473.
  • 58
    Fukata, M., Breglio, K., Chen, A., Vamadevan, A. S., Goo, T., Hsu, D., Conduah, D. et al., The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease. J. Immunol. 2008. 180: 18861894.
  • 59
    Tomita, T., Kanai, T., Fujii, T., Nemoto, Y., Okamoto, R., Tsuchiya, K., Totsuka, T. et al., MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis. J. Immunol. 2008. 180: 52915299.
  • 60
    Gibson, D. L., Ma, C., Rosenberger, C. M., Bergstrom, K. S., Valdez, Y., Huang, J. T., Khan, M. A. and Vallance, B. A., Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell Microbiol. 2008. 10: 388403.
  • 61
    Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., Takeda, K. and Akira, S., Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999. 11: 443451.
  • 62
    Markel, P., Shu, P., Ebeling, C., Carlson, G. A., Nagle, D. L., Smutko, J. S. and Moore, K. J., Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat. Genet. 1997. 17: 280284.
  • 63
    Wakeland, E., Morel, L., Achey, K., Yui, M. and Longmate, J., Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol. Today 1997. 18: 472477.