Toll-like receptor signalling in the intestinal epithelium: How bacterial recognition shapes intestinal function

Nature Reviews Immunology

Volumn 10, Issue 2, 2010, Pages 131-143

  Abreu, Maria T ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN A; LECTIN; POLYPEPTIDE ANTIBIOTIC AGENT; TOLL LIKE RECEPTOR;

CELL LINEAGE; CELL PROLIFERATION; COLON CANCER; COLON FLORA; COLORECTAL CANCER; COMMENSALISM; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INTESTINE EPITHELIUM CELL; INTESTINE FUNCTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; ANTIMICROBIAL CATIONIC PEPTIDES; BACTERIA; CELL PROLIFERATION; COLON; COLORECTAL NEOPLASMS; HOMEOSTASIS; HUMANS; INTESTINAL MUCOSA; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 75649093343     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2707     Document Type: Review

References (157)

1. Yen, T. H. & Wright, N. A. The gastrointestinal tract stem cell niche. Stem Cell Rev. 2, 203-212 (2006).
2. + intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunol. R e v. 215, 202-214 (2007).
3. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361-367 (2001).
4. 3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254-258 (2005).
5. Khan, M. A. et al. Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice. Infect. Immun. 74, 2522-2536 (2006).
6. Lebeis, S. L., Bommarius, B., Parkos, C. A., Sherman, M. A. & Kalman, D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J. Immunol. 179, 566-577 (2007).
7. Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617-620 (2009).
8. Cario, E. & Podolsky, D. K. Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68, 7010-7017 (2000).
9. Abreu, M. T. et al. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol. 167, 1609-1616 (2001).
10. Otte, J. M., Cario, E. & Podolsky, D. K. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126, 1054-1070 (2004).
11. Vamadevan, A. S. et al. Regulation of TLR4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis. Innate Immun. 26 Aug 2009 (doi:10.1177/1753425909339231).
12. Abreu, M. T. et al. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J. Biol. Chem. 277, 20431-20437 (2002).
13. Pedersen, G., Andresen, L., Matthiessen, M. W., Rask-Madsen, J. & Brynskov, J. Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin. Exp. Immunol. 141, 298-306 (2005).
14. Rehli, M. et al. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. J. Biol. Chem. 275, 9773-9781 (2000).
15. Suzuki, M., Hisamatsu, T. & Podolsky, D. K. Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex. Infect. Immun. 71, 3503-3511 (2003).
16. Mueller, T., Terada, T., Rosenberg, I. M., Shibolet, O. & Podolsky, D. K. Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells. J. Immunol. 176, 5805-5814 (2006).
17. Dalpke, A. & Heeg, K. Signal integration following Toll-like receptor triggering. Crit. Rev. Immunol. 22, 217-250 (2002).
18. Lotz, M. et al. Cytokine-mediated control of lipopolysaccharide-induced activation of small intestinal epithelial cells. Immunology 122, 306-315 (2007).
19. Lundin, A. et al. Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine. Cell. Microbiol. 10, 1093-1103 (2008)
20. Ewaschuk, J. B. et al. Surface expression of Toll-like receptor 9 is upregulated on intestinal epithelial cells in response to pathogenic bacterial DNA. Infect. Immun. 75, 2572-2579 (2007).
21. Moran, G. W., Leslie, F. C., Levison, S. E. & McLaughlin, J. T. Review: enteroendocrine cells: neglected players in gastrointestinal disorders? Therap. Adv. Gastroenterol. 1, 51-60 (2008).
22. Bogunovic, M. et al. Enteroendocrine cells express functional Toll-like receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1770-G1783 (2007).
23. Palazzo, M. et al. Activation of enteroendocrine cells via TLRs induces hormone, chemokine, and defensin secretion. J. Immunol. 178, 4296-4303 (2007).
24. Chabot, S., Wagner, J. S., Farrant, S. & Neutra, M. R. TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium. J. Immunol. 176, 4275-4283 (2006).
25. Fusunyan, R. D., Nanthakumar, N. N., Baldeon, M. E. & Walker, W. A. Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatr. Res. 49, 589-593 (2001).
26. Gewirtz, A. T., Navas, T. A., Lyons, S., Godowski, P. J. & Madara, J. L. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882-1885 (2001).
27. Rhee, S. H. et al. Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc. Natl Acad. Sci. USA 102, 13610-13615 (2005).
28. Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biol. 8, 1327-1336 (2006).
29. Bambou, J.C. et al. In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J. Biol. Chem. 279, 42984-42992 (2004).
30. Vijay-Kumar, M. et al. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 11 7, 3909-3921 (2007).
31. Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nature Immunol. 9, 769-776 (2008).
32. Lenoir, C. et al. MD-2 controls bacterial lipopolysaccharide hyporesponsiveness in human intestinal epithelial cells. Life Sci. 82, 519-528 (2008).
33. Cario, E. et al. Commensal-associated molecular patterns induce selective Toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am. J. Pathol. 160, 165-173 (2002).
34. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190-198 (2004).
35. Leifer, C. A. et al. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J. Immunol. 173, 1179-1183 (2004).
36. Akhtar, M., Watson, J. L., Nazli, A. & McKay, D. M. Bacterial DNA evokes epithelial IL-8 production by a MAPK-dependent, NF-κB-independent pathway. FASEB J. 17, 1319-1321 (2003).
37. Rachmilewitz, D. et al. Immunostimulatory oligonucleotides inhibit colonic proinflammatory cytokine production in ulcerative colitis. Inflamm. Bowel Dis. 12, 339-345 (2006).
38. Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191-1195 (2009).
39. Saitoh, S. & Miyake, K. Regulatory molecules required for nucleotide-sensing Toll-like receptors. Immunol. Rev. 227, 32-43 (2009).
40. Hornef, M. W., Frisan, T., Vandewalle, A., Normark, S. & Richter-Dahlfors, A. Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp. Med. 195, 559-570 (2002).
41. Hornef, M. W., Normark, B. H., Vandewalle, A. & Normark, S. Intracellular recognition of lipopolysaccharide by Toll-like receptor 4 in intestinal epithelial cells. J. Exp. Med. 198, 1225-1235 (2003).
42. Burns, K. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biol. 2, 346-351 (2000).
43. Zhang, G. & Ghosh, S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 277, 7059-7065 (2002).
44. Melmed, G. et al. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J. Immunol. 170, 1406-1415 (2003).
45. Steenholdt, C., Andresen, L., Pedersen, G., Hansen, A. & Brynskov, J. Expression and function of Toll-like receptor 8 and Tollip in colonic epithelial cells from patients with inflammatory bowel disease. Scand. J. Gastroenterol. 44, 195-204 (2009).
46. Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immunol. 4, 920-927 (2003).
47. Garlanda, C. et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl Acad. Sci. USA 101, 3522-3526 (2004).
48. Xiao, H. et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461-475 (2007).
49. Dubuquoy, L. et al. Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis. Gastroenterology 124, 1265-1276 (2003).
50. Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777-1782 (1999).
51. Cario, E. et al. Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. J. Immunol. 176, 4258-4266 (2006).
52. Scoville, D. H., Sato, T., He, X. C. & Li, L. Current view: intestinal stem cells and signaling. Gastroenterology 134, 849-864 (2008).
53. Abrams, G. D., Bauer, H. & Sprinz, H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Invest. 12, 355-364 (1963).
54. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99-104 (2005).
55. Nowacki, W., Cederblad, B., Renard, C., La Bonnardiere, C. & Charley, B. Age-related increase of porcine natural interferon α producing cell frequency and of interferon yield per cell. Vet. Immunol. Immunopathol. 37, 113-122 (1993).
56. Fukata, M. 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. 288, G1055-G1065 (2005).
57. Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282-1286 (2009).
58. Okayasu, I. et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694-702 (1990).
59. 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 11 8, 229-241 (2004).
60. Araki, A. et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J. Gastroenterol. 40, 16-23 (2005).
61. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453-4460 (2005).
62. Brown, S. L. et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 11 7, 258-269 (2007).
63. Ungaro, R. et al. A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1167-G1179 (2009).
64. Fort, M. M. et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 174, 6416-6423 (2005).
65. Zheng, L., Riehl, T. & Stenson, W. F. Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology 6, 2041-2051 (2009).
66. Fukata, M. et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology 131, 862-877 (2006).
67. Fukata, M. et al. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm. Bowel Dis. 15, 997-1006 (2009).
68. Giraud, A. S. X. Trefoil peptide and EGF receptor/ ligand transgenic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G501-G506 (2000).
69. Fukata, M. et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869-1881 (2007).
70. Vijay-Kumar, M. et al. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. J. Immunol. 180, 8280-8285 (2008).
71. Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359-1374 (2007).
72. Vijay-Kumar, M. et al. Activation of Toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm. Bowel Dis. 13, 856-864 (2007).
73. Rachmilewitz, D. et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122, 1428-1441 (2002).
74. Rachmilewitz, D. et al. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126, 520-528 (2004).
75. Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 11 5, 695-702 (2005).
76. Vijay-Kumar, M. et al. Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. Am. J. Pathol. 169, 1686-1700 (2006).
77. Yu, Y. et al. TLR5-mediated phosphoinositide 3-kinase activation negatively regulates flagellin-induced proinflammatory gene expression. J. Immunol. 176, 6194-6201 (2006).
78. Zeng, H. et al. Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G96-G108 (2006).
79. Mohiuddin, M. et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int. J. Radiat. Oncol. Biol. Phys. 46, 883-888 (2000).
80. Lee, C. M., Lee, R. J., Handrahan, D. L. & Sause, W. T. Comparison of late rectal toxicity from conventional versus three-dimensional conformal radiotherapy for prostate cancer: analysis of clinical and dosimetric factors. Urology 65, 114-119 (2005).
81. Manichanh, C. et al. The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am. J. Gastroenterol. 103, 1754-1761 (2008).
82. Riehl, T., Cohn, S., Tessner, T., Schloemann, S. & Stenson, W. F. Lipopolysaccharide is radioprotective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology 11 8, 1106-1116 (2000).
83. Riehl, T. E., Newberry, R. D., Lorenz, R. G. & Stenson, W. F. TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G166-G173 (2004).
84. Burdelya, L. G. et al. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226-230 (2008).
85. Sanders, C. J., Moore, D. A., Williams, I. R. & Gewirtz, A. T. Both radioresistant and hemopoietic cells promote innate and adaptive immune responses to flagellin. J. Immunol. 180, 7184-7192 (2008).
86. Persing, D. H. et al. Taking toll: lipid A mimetics as adjuvants and immunomodulators. Trends Microbiol. 10, S32-S37 (2002).
87. Soraisham, A. S., Amin, H. J., Al-Hindi, M. Y., Singhal, N. & Sauve, R. S. Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight < or =1250 g? J. Paediatr. Child Health 42, 499-504 (2006).
88. Guner, Y. S. et al. Necrotizing enterocolitis -bench to bedside: novel and emerging strategies. Semin. Pediatr. Surg. 17, 255-265 (2008).
89. Jilling, T. et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J. Immunol. 177, 3273-3282 (2006).
90. Leaphart, C. L. et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol. 179, 4808-4820 (2007).
91. Lotz, M. et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973-984 (2006).
92. Liu, Y. et al. Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G442-G450 (2009).
93. Sodhi, C. P. et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired β-catenin signaling in necrotizing enterocolitis. Gastroenterology 138, 185-196 (2009).
94. Gribar, S. C. et al. Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J. Immunol. 182, 636-646 (2009).
95. Le Mandat Schultz, A. et al. Expression of TLR-2, TLR-4, NOD2 and pNF-κB in a neonatal rat model of necrotizing enterocolitis. PLoS ONE 2, e1102 (2007).
96. Lin, H. C. et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 122, 693-700 (2008).
97. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881-884 (2001).
98. Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127, 224-238 (2004).
99. Gibson, D. L. et al. Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell. Microbiol. 10, 388-403 (2008).
100. Vora, P. et al. p-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J. Immunol. 173, 5398-5405 (2004).
101. Selsted, M. E. & Ouellette, A. J. Mammalian defensins in the antimicrobial immune response. Nature Immunol. 6, 551-557 (2005).
102. Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269-273 (2003).
103. Cash, H. L, Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126-1130 (2006).
104. Cash, H. L, Whitham, C. V. & Hooper, L. V. Refolding, purification, and characterization of human and murine RegIII proteins expressed in Escherichia coli. Protein Expr. Purif. 48, 151-159 (2006).
105. Ayabe, T et al. Secretion of microbicidal a-defensins by intestinal Paneth cells in response to bacteria. Nature Immunol. 1, 113-118 (2000).
106. Dessein, R. et al. Toll-like receptor 2 is critical for induction of Reg3(3 expression and intestinal clearance of Yersinia pseudotuberculosis. Gut 58, 771-776 (2009).
107. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731-734 (2005).
108. Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIIIy and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891-1900 (2007).
109. Vaishnava, S., Behrendt, C. L, Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858-20863 (2008).
110. Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804-807 (2008).
111. Macpherson, A. J., McCoy, K. D., Johansen, F E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11-22 (2008).
112. 2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812-826 (2007).
113. Castigli, E. et al. TACI and BAFF-R. mediate isotype switching in B cells. J. Exp. Med. 201, 35-39 (2005).
114. Shang, L. et al. Toll-like receptor signaling in small intestinal epithelium promotes B-cell recruitment and IgA production in lamina propria. Gastroenterology 135, 529-538 (2008).
115. Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841-2852 (2006).
116. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561 (2007).
117. Kim, J. Y, Kajino-Sakamoto, R., Omori, E., Jobin, C. & Ninomiya-Tsuji, J. Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis. PLoS ONE 4, e4561 (2009).
118. Kajino-Sakamoto, R. et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143-1152 (2008).
119. Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552-556 (2007).
120. Zaph, C. et al. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J. Exp. Med. 205, 2191-2198 (2008).
121. Zeuthen, L. H., Fink, L. N. & Frokiaer, H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-β. Immunology 123, 197-208 (2008).
122. + effector T cell pool and limits intestinal inflammation in a murine model of colitis. J. Immunol. 183, 2037-2044 (2009).
123. Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655-667 (2009).
124. Butler, M. et al. Modulation of dendritic cell phenotype and function in an in vitro model of the intestinal epithelium. Eur. J. Immunol. 36, 864-874 (2006).
125. Dignass, A., Lynch-Devaney, K., Kindon, H., Thim, L. & Podolsky, D. K. Trefoil peptides promote epithelial migration through a transforming growth factor β-independent pathway. J. Clin. Invest. 94, 376-383 (1994).
126. Mashimo, H., Wu, D. C., Podolsky, D. K. & Fishman, M. C. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274, 262-265 (1996).
127. Podolsky, D. K., Gerken, G., Eyking, A. & Cario, E. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology 137, 209-220 (2009).
128. Segditsas, S. & Tomlinson, I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531-7537 (2006).
129. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668-670 (1992).
130. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235-237 (1992).
131. Min mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res. 57, 812-814 (1997).
132. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124-127 (2007)
133. Phelps, R. A. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137, 623-634 (2009).
134. Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451-459 (2004).
135. Clevers, H. At the crossroads of inflammation and cancer. Cell 11 8, 671-674 (2004).
136. Yang, G. Y., Taboada, S. & Liao, J. Inflammatory bowel disease: a model of chronic inflammation-induced cancer. Methods Mol. Biol. 511, 193-233 (2009).
137. Garlanda, C. et al. Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res. 67, 6017-6021 (2007).
138. Rhee, S. H., Im, E. & Pothoulakis, C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology 135, 518-528 (2008).
139. Huang, B. et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 65, 5009-5014 (2005).
140. 2 production of colon cancer cells by inhibiting TLR4 expression and NF-κB activation. Mol. Immunol. 45, 2929-2936 (2008).
141. Tanabe, H. et al. Mouse Paneth cell secretory responses to cell surface glycolipids of virulent and attenuated pathogenic bacteria. Infect. Immun. 73, 2312-2320 (2005).
142. Ortega-Cava, C. F. et al. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 170, 3977-3985 (2003).
143. Gomariz, R. P. et al. Time-course expression of Tolllike receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP. J. Leukoc. Biol. 78, 491-502 (2005).
144. Ruiz, P. A., Shkoda, A., Kim, S. C., Sartor, R. B. & Haller, D. IL-10 gene-deficient mice lack TGF-β/Smad signaling and fail to inhibit proinflammatory gene expression in intestinal epithelial cells after the colonization with colitogenic Enterococcus faecalis. J. Immunol. 174, 2990-2999 (2005).
145. Singh, J. C. et al. Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G514-G524 (2005).
146. Gopal, R., Birdsell, D. & Monroy, F. Regulation of Tolllike receptors in intestinal epithelial cells by stress and Toxoplasma gondii infection. Parasite Immunol. 30, 563-576 (2008).
147. Furrie, E., Macfarlane, S., Thomson, G. & Macfarlane, G. T. Toll-like receptors-2,-3 and-4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology 11 5, 565-574 (2005).
148. Naik, S., Kelly, E. J., Meijer, L., Pettersson, S. & Sanderson, I. R. Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J. Pediatr. Gastroenterol. Nutr. 32, 449-453 (2001).
149. Zhou, R. B., Wei, H. M., Sun, R. & Tian, Z. G. Recognition of double-stranded RNA by TLR3 induces severe small intestinal injury in mice. J. Immunol. 178, 4548-4556 (2007).
150. Ohkawara, T. et al. Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor. Histochem. Cell Biol. 125, 575-582 (2006).
151. Reigstad, C., Lundén, G., Felin, J. & Bäckhed, F. Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota. PLoS ONE 4, e5842 (2009).
152. Neal, M. D. et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176, 3070-3079 (2006).
153. Tyrer, P., Foxwell, A. R., Cripps, A. W., Apicella, M. A. & Kyd, J. M. Microbial pattern recognition receptors mediate M-cell uptake of a Gram-negative bacterium. Infect. Immun. 74, 625-631 (2006).
154. Bashir, M. E., Louie, S., Shi, H. N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978-6987 (2004).
155. Abreu, M. T. et al. TLR signaling at the intestinal epithelial interface. J. Endotoxin Res. 9, 322-330 (2003).
156. Miyamoto, Y., Iimura, M., Kaper, J., B., Torres, A., G. & Kagnoff, M., F. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic Escherichia coli signalling of human colon epithelium in vivo. Cell. Microbiol. 8, 869-879 (2006).
157. Rumio, C. et al. Degranulation of paneth cells via Tolllike receptor 9. Am. J. Pathol. 165, 373-381 (2004).