Cellular and Molecular Life Sciences

, Volume 74, Issue 5, pp 803–826 | Cite as

Molecular pathways driving disease-specific alterations of intestinal epithelial cells

  • Rocío López-Posadas
  • Markus F. Neurath
  • Imke Atreya


Due to the fact that chronic inflammation as well as tumorigenesis in the gut is crucially impacted by the fate of intestinal epithelial cells, our article provides a comprehensive overview of the composition, function, regulation and homeostasis of the gut epithelium. In particular, we focus on those aspects which were found to be altered in the context of inflammatory bowel diseases or colorectal cancer and also discuss potential molecular targets for a disease-specific therapeutic intervention.


Intestinal epithelial cells Inflammatory bowel diseases Colorectal cancer Colitis-associated cancer Epithelial integrity 



Adherens junctions


Antimicrobial peptides


Adenomatous polyposis coli


B cell-specific Moloney murine leukemia virus integration site


Colitis-associated cancer


Columnar stem cells


Crohn’s disease


Cellular FLICE-inhibitory protein




Colorectal cancer


Doublecortin like kinase 1


Deoxyribonucleic acid


Dextran sodium sulfate


Epidermal growth factor


Epithelial-mesenchymal transition


Fas-associated protein with death domain


Fas ligand


Guanosine activating triphosphatases


Guanosine dissociation inhibitors


Guanosine diphosphate


Guanosine exchange factors




Guanosine triphosphate


Inflammatory bowel diseases


Intestinal epithelia cells






IκB kinase


Induced pluripotent stem cells


Interferon regulatory factors


Intestinal stem cell


Intestinal subepithelial myofibroblasts


Janus kinase


Junctional adhesion molecules


Leucine-rich repeat-containing G-protein-coupled receptor


TNF ligand superfamily member 14




Label-retaining cells




Mitogen-activated protein kinases


Mesenchymal-epithelial transition


Major histocompatibility complex


Myosin light-chain kinase


Microsatellite instable


Microsatellite stable


Mucin 2


Myeloid differentiation primary response gene 88


Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells


NOD-like receptor


Prostaglandin E2


Phosphatidylinositol-4,5-bisphosphate 3-kinase


Pattern recognition receptor




Resistin-like proteins


Ras homology family member


Receptor-interacting protein kinases


RIG-like receptor


Rho associated kinase


Signal transducer and activators of transcription


Tat-associated kinase


Trefoil factor 3


Transforming growth factor


T helper cell


Tight junction protein 1


TNF-like ligand 1A


Toll-like receptor


Tumor Necrosis Factor


TOLL interacting protein


Tumor necrosis factor related apoptosis inducing ligand


TIR-domain-containing adapter-inducing interferon-β


TNF-related weak inducer of apoptosis


Ulcerative colitis


Wingless-type MMTV integration site family member


X-box binding protein 1


Zona occuldens protein 1


  1. 1.
    Turner JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9:799–809PubMedCrossRefGoogle Scholar
  2. 2.
    Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54 e42 (quiz e30) PubMedCrossRefGoogle Scholar
  3. 3.
    Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Investig 117:514–521PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474:298–306PubMedCrossRefGoogle Scholar
  5. 5.
    Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT (2013) Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol 4:280PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J et al (2008) Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 294:G208–G216PubMedCrossRefGoogle Scholar
  7. 7.
    Taupin DR, Kinoshita K, Podolsky DK (2000) Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Proc Natl Acad Sci USA 97:799–804PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    McElroy SJ, Prince LS, Weitkamp JH, Reese J, Slaughter JC, Polk DB (2011) Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 301:G656–G666PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB (1990) Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 31:800–806PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102PubMedCrossRefGoogle Scholar
  11. 11.
    Lakatos PL, Lakatos L (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol WJG 14:3937–3947PubMedCrossRefGoogle Scholar
  12. 12.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108PubMedCrossRefGoogle Scholar
  13. 13.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedCrossRefGoogle Scholar
  14. 14.
    Fearon ER, Hamilton SR, Vogelstein B (1987) Clonal analysis of human colorectal tumors. Science 238:193–197PubMedCrossRefGoogle Scholar
  15. 15.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532PubMedCrossRefGoogle Scholar
  16. 16.
    Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113PubMedCrossRefGoogle Scholar
  18. 18.
    Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10:717–728PubMedCrossRefGoogle Scholar
  19. 19.
    van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Ann Rev Physiol 71:241–260CrossRefGoogle Scholar
  20. 20.
    Specian RD, Oliver MG (1991) Functional biology of intestinal goblet cells. Am J Physiol 260:C183–C193PubMedGoogle Scholar
  21. 21.
    Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9:356–368PubMedCrossRefGoogle Scholar
  22. 22.
    Ohno H (2016) Intestinal M cells. J Biochem 159:151–160PubMedCrossRefGoogle Scholar
  23. 23.
    Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. BioEssays News Rev Mole Cell Develop Biol 24:91–98CrossRefGoogle Scholar
  24. 24.
    Kvietys PR, Granger DN (2010) Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport. Ann N Y Acad Sci 1207(Suppl 1):E29–E43PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Vereecke L, Beyaert R, van Loo G (2011) Enterocyte death and intestinal barrier maintenance in homeostasis and disease. Trends Mol Med 17:584–593PubMedCrossRefGoogle Scholar
  26. 26.
    Turner JR (2006) Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application. Am J Pathol 169:1901–1909PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bjerknes M, Cheng H (1981) The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. Am J Anat 160:77–91PubMedCrossRefGoogle Scholar
  28. 28.
    Bjerknes M, Cheng H (1981) The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am J Anat 160:51–63PubMedCrossRefGoogle Scholar
  29. 29.
    Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007PubMedCrossRefGoogle Scholar
  30. 30.
    Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265PubMedCrossRefGoogle Scholar
  31. 31.
    Barker N, Tan S, Clevers H (2013) Lgr proteins in epithelial stem cell biology. Development 140:2484–2494PubMedCrossRefGoogle Scholar
  32. 32.
    Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C et al (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143:134–144PubMedCrossRefGoogle Scholar
  33. 33.
    Schepers AG, Vries R, van den Born M, van de Wetering M, Clevers H (2011) Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J 30:1104–1109PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Barker N, van de Wetering M, Clevers H (2008) The intestinal stem cell. Genes Dev 22:1856–1864PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Potten CS, Booth C, Pritchard DM (1997) The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78:219–243PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pinto LH, Pak WL (1974) Light-induced changes in photoreceptor membrane resistance and potential in Gecko retinas. II. Preparations with active lateral interactions. J Gen Physiol 64:49–69PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY et al (2012) The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 109:466–471PubMedCrossRefGoogle Scholar
  38. 38.
    Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40:915–920PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L, Kemp R et al (2013) Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495:65–69PubMedCrossRefGoogle Scholar
  40. 40.
    Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD et al (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478:255–259PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bissell MJ, Labarge MA (2005) Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 7:17–23PubMedPubMedCentralGoogle Scholar
  42. 42.
    Miyamoto S, Rosenberg DW (2011) Role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci 102:1938–1942PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rothenberg ME, Nusse Y, Kalisky T, Lee JJ, Dalerba P, Scheeren F et al (2012) Identification of a cKit(+) colonic crypt base secretory cell that supports Lgr5(+) stem cells in mice. Gastroenterology 142(1195–205):e6Google Scholar
  44. 44.
    Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M et al (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–418PubMedCrossRefGoogle Scholar
  45. 45.
    Roth S, Franken P, Sacchetti A, Kremer A, Anderson K, Sansom O et al (2012) Paneth cells in intestinal homeostasis and tissue injury. PLoS One 7:e38965PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Marson A, Foreman R, Chevalier B, Bilodeau S, Kahn M, Young RA et al (2008) Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3:132–135PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRefGoogle Scholar
  48. 48.
    De Wever O, Demetter P, Mareel M, Bracke M (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238PubMedCrossRefGoogle Scholar
  49. 49.
    Cole JW, McKalen A (1963) Studies on the morphogenesis of adenomatous polyps in the human colon. Cancer 16:998–1002PubMedCrossRefGoogle Scholar
  50. 50.
    Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Goktuna SI, Ziegler PK et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152:25–38PubMedCrossRefGoogle Scholar
  51. 51.
    Nieto MA, Cano A (2012) The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol 22:361–368PubMedCrossRefGoogle Scholar
  52. 52.
    Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG (2012) Colorectal cancer stem cells. Stem Cells 30:363–371PubMedCrossRefGoogle Scholar
  53. 53.
    Todaro M, Francipane MG, Medema JP, Stassi G (2010) Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138:2151–2162PubMedCrossRefGoogle Scholar
  54. 54.
    Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS et al (2011) EMT is the dominant program in human colon cancer. BMC Med Genomics 4:9PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Dagenais M, Douglas T, Saleh M (2014) Role of programmed necrosis and cell death in intestinal inflammation. Curr Opin Gastroenterol 30:566–575PubMedCrossRefGoogle Scholar
  56. 56.
    Gunther C, Neumann H, Neurath MF, Becker C (2013) Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 62:1062–1071PubMedCrossRefGoogle Scholar
  57. 57.
    Watson AJ (1995) Review article: manipulation of cell death—the development of novel strategies for the treatment of gastrointestinal disease. Aliment Pharmacol Ther 9:215–226PubMedCrossRefGoogle Scholar
  58. 58.
    Kanduc D, Mittelman A, Serpico R, Sinigaglia E, Sinha AA, Natale C et al (2002) Cell death: apoptosis versus necrosis (review). Int J Oncol 21:165–170PubMedGoogle Scholar
  59. 59.
    Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22:263–268PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H et al (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477:335–339PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Seneviratne D, Ma J, Tan X, Kwon YK, Muhammad E, Melhem M et al (2015) Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis. Gastroenterology 148(181–91):e17Google Scholar
  62. 62.
    Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X et al (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321PubMedCrossRefGoogle Scholar
  63. 63.
    Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ et al (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M et al (2003) A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem 278:51613–51621PubMedCrossRefGoogle Scholar
  65. 65.
    Teng X, Degterev A, Jagtap P, Xing X, Choi S, Denu R et al (2005) Structure-activity relationship study of novel necroptosis inhibitors. Bioorg Med Chem Lett 15:5039–5044PubMedCrossRefGoogle Scholar
  66. 66.
    Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J (2011) Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471:373–376PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R et al (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Grossmann J (2002) Molecular mechanisms of “detachment-induced apoptosis—Anoikis”. Apoptosis Int J Program Cell Death 7:247–260CrossRefGoogle Scholar
  69. 69.
    Brinkman BM, Hildebrand F, Kubica M, Goosens D, Del Favero J, Declercq W et al (2011) Caspase deficiency alters the murine gut microbiome. Cell Death Dis 2:e220PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T et al (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35:908–918PubMedCrossRefGoogle Scholar
  71. 71.
    Colussi PA, Kumar S (1999) Targeted disruption of caspase genes in mice: what they tell us about the functions of individual caspases in apoptosis. Immunol Cell Biol 77:58–63PubMedCrossRefGoogle Scholar
  72. 72.
    Watson AJ, Pritchard DM (2001) Lessons from genetically engineered animal models VII Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice. Am J Physiol Gastrointest Liver Physiol 278:G1–G5Google Scholar
  73. 73.
    Nakayama K, Nakayama K, Negishi I, Kuida K, Sawa H, Loh DY (1994) Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci USA 91:3700–3704PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Nakayama K, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC et al (1993) Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261:1584–1588PubMedCrossRefGoogle Scholar
  75. 75.
    Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–561PubMedCrossRefGoogle Scholar
  76. 76.
    Steinbrecher KA, Harmel-Laws E, Sitcheran R, Baldwin AS (2008) Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation. J Immunol 180:2588–2599PubMedCrossRefGoogle Scholar
  77. 77.
    Kajino-Sakamoto R, Inagaki M, Lippert E, Akira S, Robine S, Matsumoto K et al (2008) Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J Immunol 181:1143–1152PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Eckmann L, Nebelsiek T, Fingerle AA, Dann SM, Mages J, Lang R et al (2008) Opposing functions of IKKbeta during acute and chronic intestinal inflammation. Proc Natl Acad Sci USA 105:15058–15063PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedCrossRefGoogle Scholar
  80. 80.
    Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:743–756PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Glimcher LH (2010) XBP1: the last two decades. Ann Rheum Dis 69(Suppl 1):i67–i71PubMedCrossRefGoogle Scholar
  82. 82.
    Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206:1465–1472PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK (1996) Apoptosis of crypt epithelial cells in ulcerative colitis. J Pathol 180:152–159PubMedCrossRefGoogle Scholar
  84. 84.
    Hagiwara C, Tanaka M, Kudo H (2002) Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J Gastroenterol Hepatol 17:758–764PubMedCrossRefGoogle Scholar
  85. 85.
    Edelblum KL, Yan F, Yamaoka T, Polk DB (2006) Regulation of apoptosis during homeostasis and disease in the intestinal epithelium. Inflamm Bowel Dis 12:413–424PubMedCrossRefGoogle Scholar
  86. 86.
    Di Sabatino A, Ciccocioppo R, Luinetti O, Ricevuti L, Morera R, Cifone MG et al (2003) Increased enterocyte apoptosis in inflamed areas of Crohn’s disease. Dis Colon Rectum 46:1498–1507PubMedCrossRefGoogle Scholar
  87. 87.
    Dourmashkin RR, Davies H, Wells C, Shah D, Price A, O’Morain C et al (1983) Epithelial patchy necrosis in Crohn’s disease. Hum Pathol 14:643–648PubMedCrossRefGoogle Scholar
  88. 88.
    Barkla DH, Gibson PR (1999) The fate of epithelial cells in the human large intestine. Pathology 31:230–238PubMedCrossRefGoogle Scholar
  89. 89.
    Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M et al (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477:330–334PubMedCrossRefGoogle Scholar
  90. 90.
    Bedini OA, Naves A, San Miguel P, Quispe A, Guida C (2014) Metaplasic Paneth cells in ulcerative colitis. Acta Gastroenterol Latinoam 44:285–289PubMedGoogle Scholar
  91. 91.
    Simmonds N, Furman M, Karanika E, Phillips A, Bates AW (2014) Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in children. BMC Gastroenterol 14:93PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Pierdomenico M, Negroni A, Stronati L, Vitali R, Prete E, Bertin J et al (2014) Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation. Am J Gastroenterol 109:279–287PubMedCrossRefGoogle Scholar
  93. 93.
    Caprioli F, Stolfi C, Caruso R, Fina D, Sica G, Biancone L et al (2008) Transcriptional and post-translational regulation of Flip, an inhibitor of Fas-mediated apoptosis, in human gut inflammation. Gut 57:1674–1680PubMedCrossRefGoogle Scholar
  94. 94.
    Bullen TF, Forrest S, Campbell F, Dodson AR, Hershman MJ, Pritchard DM et al (2006) Characterization of epithelial cell shedding from human small intestine. Lab Invest J Tech Methods Pathol 86:1052–1063CrossRefGoogle Scholar
  95. 95.
    Marchiando AM, Shen L, Graham WV, Edelblum KL, Duckworth CA, Guan Y et al (2011) The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology 140(1208–18):e1–e2Google Scholar
  96. 96.
    Williams JM, Duckworth CA, Watson AJ, Frey MR, Miguel JC, Burkitt MD et al (2013) A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Disease Models Mech 6:1388–1399CrossRefGoogle Scholar
  97. 97.
    Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA et al (2012) Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484:546–549PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Guan Y, Watson AJ, Marchiando AM, Bradford E, Shen L, Turner JR et al (2011) Redistribution of the tight junction protein ZO-1 during physiological shedding of mouse intestinal epithelial cells. Am J Physiol Cell Physiol 300:C1404–C1414PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Marinari E, Mehonic A, Curran S, Gale J, Duke T, Baum B (2012) Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484:542–545PubMedCrossRefGoogle Scholar
  100. 100.
    Rosenblatt J, Raff MC, Cramer LP (2001) An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol CB 11:1847–1857PubMedCrossRefGoogle Scholar
  101. 101.
    Kiesslich R, Goetz M, Angus EM, Hu Q, Guan Y, Potten C et al (2007) Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology 133:1769–1778PubMedCrossRefGoogle Scholar
  102. 102.
    Watson AJ, Chu S, Sieck L, Gerasimenko O, Bullen T, Campbell F et al (2005) Epithelial barrier function in vivo is sustained despite gaps in epithelial layers. Gastroenterology 129:902–912PubMedCrossRefGoogle Scholar
  103. 103.
    Kiesslich R, Duckworth CA, Moussata D, Gloeckner A, Lim LG, Goetz M et al (2012) Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 61:1146–1153PubMedCrossRefGoogle Scholar
  104. 104.
    Koch S, Nusrat A (2009) Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann N Y Acad Sci 1165:220–227PubMedCrossRefGoogle Scholar
  105. 105.
    Niessen CM (2007) Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127:2525–2532PubMedCrossRefGoogle Scholar
  106. 106.
    Gumbiner B (1987) Structure, biochemistry, and assembly of epithelial tight junctions. Am J Physiol 253:C749–C758PubMedGoogle Scholar
  107. 107.
    Cunningham KE, Turner JR (2012) Myosin light chain kinase: pulling the strings of epithelial tight junction function. Ann N Y Acad Sci 1258:34–42PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Anderson JM, Van Itallie CM, Fanning AS (2004) Setting up a selective barrier at the apical junction complex. Curr Opin Cell Biol 16:140–145PubMedCrossRefGoogle Scholar
  109. 109.
    Perez-Moreno M, Jamora C, Fuchs E (2003) Sticky business: orchestrating cellular signals at adherens junctions. Cell 112:535–548PubMedCrossRefGoogle Scholar
  110. 110.
    Gates J, Peifer M (2005) Can 1000 reviews be wrong? Actin, alpha-Catenin, and adherens junctions. Cell 123:769–772PubMedCrossRefGoogle Scholar
  111. 111.
    Dusek RL, Godsel LM, Green KJ (2007) Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion. J Dermatol Sci 45:7–21PubMedCrossRefGoogle Scholar
  112. 112.
    Mese G, Richard G, White TW (2007) Gap junctions: basic structure and function. J Invest Dermatol 127:2516–2524PubMedCrossRefGoogle Scholar
  113. 113.
    Ivanov AI, Parkos CA, Nusrat A (2010) Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol 177:512–524PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Rodgers LS, Fanning AS (2011) Regulation of epithelial permeability by the actin cytoskeleton. Cytoskeleton 68:653–660PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Nusrat A, von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA (2001) Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect Immun 69:1329–1336PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Betanzos A, Javier-Reyna R, Garcia-Rivera G, Banuelos C, Gonzalez-Mariscal L, Schnoor M et al (2013) The EhCPADH112 complex of Entamoeba histolytica interacts with tight junction proteins occludin and claudin-1 to produce epithelial damage. PLoS One 8:e65100PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Shifflett DE, Clayburgh DR, Koutsouris A, Turner JR, Hecht GA (2005) Enteropathogenic E. coli disrupts tight junction barrier function and structure in vivo. Lab Invest J Tech Methods Pathol 85:1308–1324CrossRefGoogle Scholar
  118. 118.
    Heasman SJ, Ridley AJ (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9:690–701PubMedCrossRefGoogle Scholar
  119. 119.
    Menke A, Giehl K (2012) Regulation of adherens junctions by Rho GTPases and p120-catenin. Arch Biochem Biophys 524:48–55PubMedCrossRefGoogle Scholar
  120. 120.
    Hollander D (1993) Permeability in Crohn’s disease: altered barrier functions in healthy relatives? Gastroenterology 104:1848–1851PubMedCrossRefGoogle Scholar
  121. 121.
    Ukabam SO, Clamp JR, Cooper BT (1983) Abnormal small intestinal permeability to sugars in patients with Crohn’s disease of the terminal ileum and colon. Digestion 27:70–74PubMedCrossRefGoogle Scholar
  122. 122.
    Mankertz J, Schulzke JD (2007) Altered permeability in inflammatory bowel disease: pathophysiology and clinical implications. Curr Opin Gastroenterol 23:379–383PubMedCrossRefGoogle Scholar
  123. 123.
    Yacyshyn BR, Meddings JB (1995) CD45RO expression on circulating CD19+ B cells in Crohn’s disease correlates with intestinal permeability. Gastroenterology 108:132–137PubMedCrossRefGoogle Scholar
  124. 124.
    D’Inca R, Di Leo V, Corrao G, Martines D, D’Odorico A, Mestriner C et al (1999) Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol 94:2956–2960PubMedCrossRefGoogle Scholar
  125. 125.
    Tamura A, Kitano Y, Hata M, Katsuno T, Moriwaki K, Sasaki H et al (2008) Megaintestine in claudin-15-deficient mice. Gastroenterology 134:523–534PubMedCrossRefGoogle Scholar
  126. 126.
    Khounlotham M, Kim W, Peatman E, Nava P, Medina-Contreras O, Addis C et al (2012) Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. Immunity 37:563–573PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Schulzke JD, Gitter AH, Mankertz J, Spiegel S, Seidler U, Amasheh S et al (2005) Epithelial transport and barrier function in occludin-deficient mice. Biochim Biophys Acta 1669:34–42PubMedCrossRefGoogle Scholar
  128. 128.
    Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK et al (2014) Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut 63:622–634PubMedCrossRefGoogle Scholar
  129. 129.
    Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L et al (2014) Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One 9:e85345PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B et al (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129:550–564PubMedCrossRefGoogle Scholar
  131. 131.
    Kawashima R, Kawamura YI, Oshio T, Son A, Yamazaki M, Hagiwara T et al (2011) Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 141(2119–29):e8Google Scholar
  132. 132.
    Franze E, Caruso R, Stolfi C, Sarra M, Cupi ML, Ascolani M et al (2013) High expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a sheddase for TNF-alpha in the mucosa of patients with inflammatory bowel diseases. Inflamm Bowel Dis 19:501–511PubMedCrossRefGoogle Scholar
  133. 133.
    Blair SA, Kane SV, Clayburgh DR, Turner JR (2006) Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab Invest J Tech Methods Pathol 86:191–201CrossRefGoogle Scholar
  134. 134.
    Wang F, Schwarz BT, Graham WV, Wang Y, Su L, Clayburgh DR et al (2006) IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 131:1153–1163PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Schmitz H, Barmeyer C, Fromm M, Runkel N, Foss HD, Bentzel CJ et al (1999) Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 116:301–309PubMedCrossRefGoogle Scholar
  136. 136.
    Irvine EJ, Marshall JK (2000) Increased intestinal permeability precedes the onset of Crohn’s disease in a subject with familial risk. Gastroenterology 119:1740–1744PubMedCrossRefGoogle Scholar
  137. 137.
    Peeters M, Geypens B, Claus D, Nevens H, Ghoos Y, Verbeke G et al (1997) Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology 113:802–807PubMedCrossRefGoogle Scholar
  138. 138.
    Katz KD, Hollander D, Vadheim CM, McElree C, Delahunty T, Dadufalza VD et al (1989) Intestinal permeability in patients with Crohn’s disease and their healthy relatives. Gastroenterology 97:927–931PubMedCrossRefGoogle Scholar
  139. 139.
    Wells JM, Rossi O, Meijerink M, van Baarlen P (2011) Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci USA 108(Suppl 1):4607–4614PubMedCrossRefGoogle Scholar
  140. 140.
    Wittkopf N, Neurath MF, Becker C (2014) Immune-epithelial crosstalk at the intestinal surface. J Gastroenterol 49:375–387PubMedCrossRefGoogle Scholar
  141. 141.
    Finegold SM, Attebery HR, Sutter VL (1974) Effect of diet on human fecal flora: comparison of Japanese and American diets. Am J Clin Nutr 27:1456–1469PubMedGoogle Scholar
  142. 142.
    Baumler AJ, Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85–93PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E (2016) Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 22:1137–1150PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V et al (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–1283PubMedCrossRefGoogle Scholar
  145. 145.
    Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N et al (2011) High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 11:7PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Thayer WR Jr, Coutu JA, Chiodini RJ, Van Kruiningen HJ, Merkal RS (1984) Possible role of mycobacteria in inflammatory bowel disease. II. Mycobacterial antibodies in Crohn’s disease. Dig Dis Sci 29:1080–1085PubMedCrossRefGoogle Scholar
  147. 147.
    Lamhonwah AM, Ackerley C, Onizuka R, Tilups A, Lamhonwah D, Chung C et al (2005) Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn’s disease at 5q31. Biochem Biophy Res Commun 337:1165–1175CrossRefGoogle Scholar
  148. 148.
    Szilagyi A, Gerson M, Mendelson J, Yusuf NA (1985) Salmonella infections complicating inflammatory bowel disease. J Clin Gastroenterol 7:251–255PubMedCrossRefGoogle Scholar
  149. 149.
    Contractor NV, Bassiri H, Reya T, Park AY, Baumgart DC, Wasik MA et al (1998) Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J Immunol 160:385–394PubMedGoogle Scholar
  150. 150.
    Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernandez-Sueiro JL et al (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359–2364PubMedCrossRefGoogle Scholar
  151. 151.
    Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S et al (2002) Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295:1726–1729PubMedCrossRefGoogle Scholar
  152. 152.
    Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB et al (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131:117–129PubMedCrossRefGoogle Scholar
  153. 153.
    Artis D, Wang ML, Keilbaugh SA, He W, Brenes M, Swain GP et al (2004) RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 101:13596–13600PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Nair MG, Guild KJ, Du Y, Zaph C, Yancopoulos GD, Valenzuela DM et al (2008) Goblet cell-derived resistin-like molecule beta augments CD4+ T cell production of IFN-gamma and infection-induced intestinal inflammation. J Immunol 181:4709–4715PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Wang S, Thacker PA, Watford M, Qiao S (2015) Functions of antimicrobial peptides in gut homeostasis. Curr Protein Pept Sci 16:582–591PubMedCrossRefGoogle Scholar
  156. 156.
    Cunliffe RN, Mahida YR (2004) Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol 75:49–58PubMedCrossRefGoogle Scholar
  157. 157.
    Gersemann M, Wehkamp J, Stange EF (2012) Innate immune dysfunction in inflammatory bowel disease. J Intern Med 271:421–428PubMedCrossRefGoogle Scholar
  158. 158.
    Wehkamp J, Koslowski M, Wang G, Stange EF (2008) Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunol 1(Suppl 1):S67–S74PubMedCrossRefGoogle Scholar
  159. 159.
    Koon HW, Shih DQ, Chen J, Bakirtzi K, Hing TC, Law I et al (2011) Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology 141(1852–63):e1–e3Google Scholar
  160. 160.
    Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 102:18129–18134PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Courth LF, Ostaff MJ, Mailander-Sanchez D, Malek NP, Stange EF, Wehkamp J (2015) Crohn’s disease-derived monocytes fail to induce Paneth cell defensins. Proc Natl Acad Sci USA 112:14000–14005PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Wehkamp J, Harder J, Weichenthal M, Mueller O, Herrlinger KR, Fellermann K et al (2003) Inducible and constitutive beta-defensins are differentially expressed in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 9:215–223PubMedCrossRefGoogle Scholar
  163. 163.
    Strugala V, Dettmar PW, Pearson JP (2008) Thickness and continuity of the adherent colonic mucus barrier in active and quiescent ulcerative colitis and Crohn’s disease. Int J Clin Pract 62:762–769PubMedCrossRefGoogle Scholar
  164. 164.
    Rohrl J, Geissler EK, Hehlgans T (2012) Friend or foe: a novel role of beta-defensins in tumor development. Oncoimmunology 1:1159–1160PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Rohrl J, Huber B, Koehl GE, Geissler EK, Hehlgans T (2012) Mouse beta-defensin 14 (Defb14) promotes tumor growth by inducing angiogenesis in a CCR6-dependent manner. J Immunol 188:4931–4939PubMedCrossRefGoogle Scholar
  166. 166.
    Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650PubMedCrossRefGoogle Scholar
  167. 167.
    Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 14:546–558PubMedCrossRefGoogle Scholar
  168. 168.
    Abreu MT (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10:131–144PubMedCrossRefGoogle Scholar
  169. 169.
    Peterson LW, Artis D (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14:141–153PubMedCrossRefGoogle Scholar
  170. 170.
    Madara JL, Stafford J (1989) Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Investig 83:724–727PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA et al (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286:G367–G376PubMedCrossRefGoogle Scholar
  172. 172.
    Ceponis PJ, Botelho F, Richards CD, McKay DM (2000) Interleukins 4 and 13 increase intestinal epithelial permeability by a phosphatidylinositol 3-kinase pathway. Lack of evidence for STAT 6 involvement. J Biol Chem 275:29132–29137PubMedCrossRefGoogle Scholar
  173. 173.
    Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167:1882–1885PubMedCrossRefGoogle Scholar
  174. 174.
    Rhee SH, Im E, Riegler M, Kokkotou E, O’Brien M, Pothoulakis C (2005) Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc Natl Acad Sci USA 102:13610–13615PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT et al (2006) Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 8:1327–1336PubMedCrossRefGoogle Scholar
  176. 176.
    Cario E, Podolsky DK (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010–7017PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S et al (2007) Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133:1869–1881PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS (2005) Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA 102:99–104PubMedCrossRefGoogle Scholar
  179. 179.
    Vijay-Kumar M, Wu H, Aitken J, Kolachala VL, Neish AS, Sitaraman SV et al (2007) Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 13:856–864PubMedCrossRefGoogle Scholar
  180. 180.
    Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B et al (2004) Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126:520–528PubMedCrossRefGoogle Scholar
  181. 181.
    Vijay-Kumar M, Aitken JD, Sanders CJ, Frias A, Sloane VM, Xu J et al (2008) Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. J Immunol 180:8280–8285PubMedCrossRefGoogle Scholar
  182. 182.
    Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D et al (2007) The Toll–interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26:461–475PubMedCrossRefGoogle Scholar
  183. 183.
    Vereecke L, Sze M, Mc Guire C, Rogiers B, Chu Y, Schmidt-Supprian M et al (2010) Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J Exp Med 207:1513–1523PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Steenholdt C, Andresen L, Pedersen G, Hansen A, Brynskov J (2009) Expression and function of toll-like receptor 8 and Tollip in colonic epithelial cells from patients with inflammatory bowel disease. Scand J Gastroenterol 44:195–204PubMedCrossRefGoogle Scholar
  185. 185.
    Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317:124–127PubMedCrossRefGoogle Scholar
  186. 186.
    Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C et al (2010) Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci USA 107:21635–21640PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J et al (2011) The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20:649–660PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Lin XP, Almqvist N, Telemo E (2005) Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes. Blood Cells Mol Dis 35:122–128PubMedCrossRefGoogle Scholar
  189. 189.
    Hershberg RM, Cho DH, Youakim A, Bradley MB, Lee JS, Framson PE et al (1998) Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells. J Clin Investig 102:792–803PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Nakazawa A, Dotan I, Brimnes J, Allez M, Shao L, Tsushima F et al (2004) The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells. Gastroenterology 126:1347–1357PubMedCrossRefGoogle Scholar
  191. 191.
    Hershberg RM, Framson PE, Cho DH, Lee LY, Kovats S, Beitz J et al (1997) Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. J Clin Investig 100:204–215PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Buning J, Schmitz M, Repenning B, Ludwig D, Schmidt MA, Strobel S et al (2005) Interferon-gamma mediates antigen trafficking to MHC class II-positive late endosomes of enterocytes. Eur J Immunol 35:831–842PubMedCrossRefGoogle Scholar
  193. 193.
    Bar F, Sina C, Hundorfean G, Pagel R, Lehnert H, Fellermann K et al (2013) Inflammatory bowel diseases influence major histocompatibility complex class I (MHC I) and II compartments in intestinal epithelial cells. Clin Exp Immunol 172:280–289PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Thelemann C, Eren RO, Coutaz M, Brasseit J, Bouzourene H, Rosa M et al (2014) Interferon-gamma induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis. PLoS One 9:e86844PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756PubMedCrossRefGoogle Scholar
  196. 196.
    Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Ann Rev Immunol 23:23–68CrossRefGoogle Scholar
  197. 197.
    Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9:271–285PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Watson AJ, Hughes KR (2012) TNF-alpha-induced intestinal epithelial cell shedding: implications for intestinal barrier function. Ann N Y Acad Sci 1258:1–8PubMedCrossRefGoogle Scholar
  199. 199.
    Aggarwal BB, Gupta SC, Kim JH (2012) Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood 119:651–665PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Hampe J, Shaw SH, Saiz R, Leysens N, Lantermann A, Mascheretti S et al (1999) Linkage of inflammatory bowel disease to human chromosome 6p. Am J Hum Genet 65:1647–1655PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Dechairo B, Dimon C, van Heel D, Mackay I, Edwards M, Scambler P et al (2001) Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3). Eur J Human Genet EJHG 9:627–633PubMedCrossRefGoogle Scholar
  202. 202.
    Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM et al (2000) Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 66:1863–1870PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Dionne S, Hiscott J, D’Agata I, Duhaime A, Seidman EG (1997) Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies. Dig Dis Sci 42:1557–1566PubMedCrossRefGoogle Scholar
  204. 204.
    Matsuda R, Koide T, Tokoro C, Yamamoto T, Godai T, Morohashi T et al (2009) Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naive ulcerative colitis during active and quiescent disease. Inflamm Bowel Dis 15:328–334PubMedCrossRefGoogle Scholar
  205. 205.
    Komatsu M, Kobayashi D, Saito K, Furuya D, Yagihashi A, Araake H et al (2001) Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR. Clin Chem 47:1297–1301PubMedGoogle Scholar
  206. 206.
    Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT (1991) Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 32:913–917PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Maeda M, Watanabe N, Neda H, Yamauchi N, Okamoto T, Sasaki H et al (1992) Serum tumor necrosis factor activity in inflammatory bowel disease. Immunopharmacol Immunotoxicol 14:451–461PubMedCrossRefGoogle Scholar
  208. 208.
    Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT (1992) Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339:89–91PubMedCrossRefGoogle Scholar
  209. 209.
    MacDonald TT, Hutchings P, Choy MY, Murch S, Cooke A (1990) Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 81:301–305PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Reimund JM, Wittersheim C, Dumont S, Muller CD, Baumann R, Poindron P et al (1996) Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease. J Clin Immunol 16:144–150PubMedCrossRefGoogle Scholar
  211. 211.
    Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P et al (1994) Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 106:1455–1466PubMedCrossRefGoogle Scholar
  212. 212.
    Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT (1993) Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 34:1705–1709PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Stevens C, Walz G, Singaram C, Lipman ML, Zanker B, Muggia A et al (1992) Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci 37:818–826PubMedCrossRefGoogle Scholar
  214. 214.
    Hyams JS, Treem WR, Eddy E, Wyzga N, Moore RE (1991) Tumor necrosis factor-alpha is not elevated in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 12:233–236PubMedCrossRefGoogle Scholar
  215. 215.
    Owczarek D, Cibor D, Glowacki MK, Ciesla A, Mach P (2012) TNF-alpha and soluble forms of TNF receptors 1 and 2 in the serum of patients with Crohn’s disease and ulcerative colitis. Pol Arch Med Wewn 122:616–623PubMedGoogle Scholar
  216. 216.
    Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ et al (2002) Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice. Gastroenterology 122:134–144PubMedCrossRefGoogle Scholar
  217. 217.
    Holtmann MH, Douni E, Schutz M, Zeller G, Mudter J, Lehr HA et al (2002) Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn’s disease and promotes experimental colitis in vivo. Eur J Immunol 32:3142–3151PubMedCrossRefGoogle Scholar
  218. 218.
    Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387–398PubMedCrossRefGoogle Scholar
  219. 219.
    Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G et al (2002) Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol 97:2000–2004PubMedCrossRefGoogle Scholar
  220. 220.
    Fries W, Muja C, Crisafulli C, Costantino G, Longo G, Cuzzocrea S et al (2008) Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis. Int J Med Sci 5:169–180PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Fischer A, Gluth M, Pape UF, Wiedenmann B, Theuring F, Baumgart DC (2013) Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-alpha on tight junction proteins and signaling pathways in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 304:G970–G979PubMedCrossRefGoogle Scholar
  222. 222.
    Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S et al (2003) Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology 125:47–57PubMedCrossRefGoogle Scholar
  223. 223.
    Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717–1725PubMedCrossRefGoogle Scholar
  224. 224.
    Novotny-Smith CL, Zorbas MA, McIsaac AM, Irimura T, Boman BM, Yeoman LC et al (1993) Down-modulation of epidermal growth factor receptor accompanies TNF-induced differentiation of the DiFi human adenocarcinoma cell line toward a goblet-like phenotype. J Cell Physiol 157:253–262PubMedCrossRefGoogle Scholar
  225. 225.
    Iwashita J, Sato Y, Sugaya H, Takahashi N, Sasaki H, Abe T (2003) mRNA of MUC2 is stimulated by IL-4, IL-13 or TNF-alpha through a mitogen-activated protein kinase pathway in human colon cancer cells. Immunol Cell Biol 81:275–282PubMedCrossRefGoogle Scholar
  226. 226.
    Freour T, Jarry A, Bach-Ngohou K, Dejoie T, Bou-Hanna C, Denis MG et al (2009) TACE inhibition amplifies TNF-alpha-mediated colonic epithelial barrier disruption. Int J Mol Med 23:41–48PubMedGoogle Scholar
  227. 227.
    Su L, Nalle SC, Shen L, Turner ES, Singh G, Breskin LA et al (2013) TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology 145:407–415PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR (2005) Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am J Pathol 166:409–419PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Cesaro A, Abakar-Mahamat A, Brest P, Lassalle S, Selva E, Filippi J et al (2009) Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 296:G1332–G1343PubMedCrossRefGoogle Scholar
  230. 230.
    Van Hauwermeiren F, Armaka M, Karagianni N, Kranidioti K, Vandenbroucke RE, Loges S et al (2013) Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. J Clin Investig 123:2590–2603PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Goretsky T, Dirisina R, Sinh P, Mittal N, Managlia E, Williams DB et al (2012) p53 mediates TNF-induced epithelial cell apoptosis in IBD. Am J Pathol 181:1306–1315PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Piguet PF, Vesin C, Guo J, Donati Y, Barazzone C (1998) TNF-induced enterocyte apoptosis in mice is mediated by the TNF receptor 1 and does not require p53. Eur J Immunol 28:3499–3505PubMedCrossRefGoogle Scholar
  233. 233.
    Hilliard VC, Frey MR, Dempsey PJ, Peek RM Jr, Polk DB (2011) TNF-alpha converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival. Am J Physiol Gastrointest Liver Physiol 301:G338–G346PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Frey MR, Edelblum KL, Mullane MT, Liang D, Polk DB (2009) The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology 136:217–226PubMedCrossRefGoogle Scholar
  235. 235.
    Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR et al (2011) TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 301:G220–G229PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Bamias G, Corridoni D, Pizarro TT, Cominelli F (2012) New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation. Cytokine 59:451–459PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Meylan F, Richard AC, Siegel RM (2011) TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunol Rev 244:188–196PubMedCrossRefGoogle Scholar
  238. 238.
    Ueyama H, Kiyohara T, Sawada N, Isozaki K, Kitamura S, Kondo S et al (1998) High Fas ligand expression on lymphocytes in lesions of ulcerative colitis. Gut 43:48–55PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Yukawa M, Iizuka M, Horie Y, Yoneyama K, Shirasaka T, Itou H et al (2002) Systemic and local evidence of increased Fas-mediated apoptosis in ulcerative colitis. Int J Colorectal Dis 17:70–76PubMedCrossRefGoogle Scholar
  240. 240.
    Souza HS, Tortori CJ, Castelo-Branco MT, Carvalho AT, Margallo VS, Delgado CF et al (2005) Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways. Int J Colorectal Dis 20:277–286PubMedCrossRefGoogle Scholar
  241. 241.
    Cohavy O, Zhou J, Ware CF, Targan SR (2005) LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signaling. J Immunol 174:646–653PubMedCrossRefGoogle Scholar
  242. 242.
    Begue B, Wajant H, Bambou JC, Dubuquoy L, Siegmund D, Beaulieu JF et al (2006) Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions. Gastroenterology 130:1962–1974PubMedCrossRefGoogle Scholar
  243. 243.
    Witte E, Witte K, Warszawska K, Sabat R, Wolk K (2010) Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev 21:365–379PubMedCrossRefGoogle Scholar
  244. 244.
    Atreya R, Neurath MF (2005) Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol 28:187–196PubMedCrossRefGoogle Scholar
  245. 245.
    Lenardo MJ, Baltimore D (1989) NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58:227–229PubMedCrossRefGoogle Scholar
  246. 246.
    Gloire G, Dejardin E, Piette J (2006) Extending the nuclear roles of IkappaB kinase subunits. Biochem Pharmacol 72:1081–1089PubMedCrossRefGoogle Scholar
  247. 247.
    Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242:540–546PubMedCrossRefGoogle Scholar
  248. 248.
    Greten FR, Karin M (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 206:193–199PubMedCrossRefGoogle Scholar
  249. 249.
    Huxford T, Malek S, Ghosh G (1999) Structure and mechanism in NF-kappa B/I kappa B signaling. Cold Spring Harb Symp Quant Biol 64:533–540PubMedCrossRefGoogle Scholar
  250. 250.
    Neurath MF, Pettersson S, Meyer zum Buschenfelde KH, Strober W (1996) Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2:998–1004PubMedCrossRefGoogle Scholar
  251. 251.
    Conner EM, Brand S, Davis JM, Laroux FS, Palombella VJ, Fuseler JW et al (1997) Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis. J Pharmacol Exp Ther 282:1615–1622PubMedGoogle Scholar
  252. 252.
    Herfarth H, Brand K, Rath HC, Rogler G, Scholmerich J, Falk W (2000) Nuclear factor-kappa B activity and intestinal inflammation in dextran sulphate sodium (DSS)-induced colitis in mice is suppressed by gliotoxin. Clin Exp Immunol 120:59–65PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Jobin C, Panja A, Hellerbrand C, Iimuro Y, Didonato J, Brenner DA et al (1998) Inhibition of proinflammatory molecule production by adenovirus-mediated expression of a nuclear factor kappaB super-repressor in human intestinal epithelial cells. J Immunol 160:410–418PubMedGoogle Scholar
  254. 254.
    Jobin C, Hellerbrand C, Licato LL, Brenner DA, Sartor RB (1998) Mediation by NF-kappa B of cytokine induced expression of intercellular adhesion molecule 1 (ICAM-1) in an intestinal epithelial cell line, a process blocked by proteasome inhibitors. Gut 42:779–787PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T et al (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369PubMedCrossRefGoogle Scholar
  256. 256.
    Zaph C, Troy AE, Taylor BC, Berman-Booty LD, Guild KJ, Du Y et al (2007) Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446:552–556PubMedCrossRefGoogle Scholar
  257. 257.
    Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Lees AB, Goldstine HH (1961) Communication channels. Science 134:527–529PubMedCrossRefGoogle Scholar
  259. 259.
    Cenit MC, Alcina A, Marquez A, Mendoza JL, Diaz-Rubio M, de las Heras V et al (2010) STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun 11:264–268PubMedCrossRefGoogle Scholar
  260. 260.
    Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 22:83–89PubMedCrossRefGoogle Scholar
  261. 261.
    Wirtz S, Finotto S, Kanzler S, Lohse AW, Blessing M, Lehr HA et al (1999) Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens. J Immunol 162:1884–1888PubMedGoogle Scholar
  262. 262.
    Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I et al (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–49PubMedCrossRefGoogle Scholar
  263. 263.
    Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S et al (2000) 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 6:583–588PubMedCrossRefGoogle Scholar
  264. 264.
    Kobayashi M, Kweon MN, Kuwata H, Schreiber RD, Kiyono H, Takeda K et al (2003) Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J Clin Investig 111:1297–1308PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Li Y, de Haar C, Chen M, Deuring J, Gerrits MM, Smits R et al (2010) Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 59:227–235PubMedCrossRefGoogle Scholar
  266. 266.
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK et al (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Investig 118:534–544PubMedPubMedCentralGoogle Scholar
  267. 267.
    Backert I, Koralov SB, Wirtz S, Kitowski V, Billmeier U, Martini E et al (2014) STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis. J Immunol 193:3779–3791PubMedCrossRefGoogle Scholar
  268. 268.
    Du W, Hong J, Wang YC, Zhang YJ, Wang P, Su WY et al (2012) Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway. J Cell Mol Med 16:1878–1888PubMedPubMedCentralCrossRefGoogle Scholar
  269. 269.
    Nguyen AV, Wu YY, Liu Q, Wang D, Nguyen S, Loh R et al (2013) STAT3 in epithelial cells regulates inflammation and tumor progression to malignant state in colon. Neoplasia 15:998–1008PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL et al (2013) Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 210:917–931PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Thompson CL, Plummer SJ, Tucker TC, Casey G, Li L (2010) Interleukin-22 genetic polymorphisms and risk of colon cancer. Cancer Causes Control CCC 21:1165–1170PubMedCrossRefGoogle Scholar
  272. 272.
    Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17:1709–1713PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337CrossRefGoogle Scholar
  274. 274.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y et al (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847PubMedCrossRefGoogle Scholar
  275. 275.
    Krausova M, Korinek V (2014) Wnt signaling in adult intestinal stem cells and cancer. Cell Signal 26:570–579PubMedCrossRefGoogle Scholar
  276. 276.
    Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP et al (2012) Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell 149:1245–1256PubMedCrossRefGoogle Scholar
  277. 277.
    Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R et al (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642PubMedCrossRefGoogle Scholar
  278. 278.
    Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V et al (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86:391–399PubMedCrossRefGoogle Scholar
  279. 279.
    de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H et al (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476:293–297PubMedCrossRefGoogle Scholar
  280. 280.
    Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D et al (2011) LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Rep 12:1055–1061PubMedPubMedCentralCrossRefGoogle Scholar
  281. 281.
    Robles AI, Traverso G, Zhang M, Roberts NJ, Khan MA, Joseph C et al (2016) Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 150:931–943PubMedCrossRefGoogle Scholar
  282. 282.
    Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253:661–665PubMedCrossRefGoogle Scholar
  283. 283.
    Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A et al (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669PubMedCrossRefGoogle Scholar
  284. 284.
    Gaspar C, Fodde R (2004) APC dosage effects in tumorigenesis and stem cell differentiation. Int J Develop Biol 48:377–386CrossRefGoogle Scholar
  285. 285.
    Fearon ER (2011) Molecular genetics of colorectal cancer. Ann Rev Pathol 6:479–507CrossRefGoogle Scholar
  286. 286.
    Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422PubMedCrossRefGoogle Scholar
  287. 287.
    Rawson JB, Manno M, Mrkonjic M, Daftary D, Dicks E, Buchanan DD et al (2011) Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients. Carcinogenesis 32:741–747PubMedPubMedCentralCrossRefGoogle Scholar
  288. 288.
    Andrianifahanana M, Moniaux N, Schmied BM, Ringel J, Friess H, Hollingsworth MA et al (2001) Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clin Cancer Res Off J Am Assoc Cancer Res 7:4033–4040Google Scholar
  289. 289.
    Renaud F, Mariette C, Vincent A, Wacrenier A, Maunoury V, Leclerc J et al (2016) The serrated neoplasia pathway of colorectal tumors: identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential. Int J Cancer 138:1472–1481PubMedCrossRefGoogle Scholar
  290. 290.
    Kesari MV, Gaopande VL, Joshi AR, Babanagare SV, Gogate BP, Khadilkar AV (2015) Immunohistochemical study of MUC1, MUC2 and MUC5AC in colorectal carcinoma and review of literature. Indian J Gastroenterol Off J Indian Soc Gastroenterol 34:63–67CrossRefGoogle Scholar
  291. 291.
    Biemer-Huttmann AE, Walsh MD, McGuckin MA, Ajioka Y, Watanabe H, Leggett BA et al (1999) Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum. J Histochem Cytochem Off J Histochem Soc 47:1039–1048CrossRefGoogle Scholar
  292. 292.
    Shanmugam C, Jhala NC, Katkoori VR, Wan W, Meleth S, Grizzle WE et al (2010) Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer 116:3577–3586PubMedPubMedCentralCrossRefGoogle Scholar
  293. 293.
    Ogata S, Uehara H, Chen A, Itzkowitz SH (1992) Mucin gene expression in colonic tissues and cell lines. Cancer Res 52:5971–5978PubMedGoogle Scholar
  294. 294.
    Imai Y, Yamagishi H, Fukuda K, Ono Y, Inoue T, Ueda Y (2013) Differential mucin phenotypes and their significance in a variation of colorectal carcinoma. World J Gastroenterol WJG 19:3957–3968PubMedCrossRefGoogle Scholar
  295. 295.
    Pai P, Rachagani S, Dhawan P, Batra SK (2016) Mucins and Wnt/beta-catenin signaling in gastrointestinal cancers: an unholy nexus. Carcinogenesis 37:223–232PubMedCrossRefGoogle Scholar
  296. 296.
    van de Wetering M, Oving I, Muncan V, Pon Fong MT, Brantjes H, van Leenen D et al (2003) Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector. EMBO Rep 4:609–615PubMedPubMedCentralCrossRefGoogle Scholar
  297. 297.
    van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250PubMedCrossRefGoogle Scholar
  298. 298.
    Caderni G, Femia AP, Giannini A, Favuzza A, Luceri C, Salvadori M et al (2003) Identification of mucin-depleted foci in the unsectioned colon of azoxymethane-treated rats: correlation with carcinogenesis. Cancer Res 63:2388–2392PubMedGoogle Scholar
  299. 299.
    Citalan-Madrid AF, Garcia-Ponce A, Vargas-Robles H, Betanzos A, Schnoor M (2013) Small GTPases of the Ras superfamily regulate intestinal epithelial homeostasis and barrier function via common and unique mechanisms. Tissue Barr 1:e26938CrossRefGoogle Scholar
  300. 300.
    Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93:269–309PubMedCrossRefGoogle Scholar
  301. 301.
    Garcia-Mata R, Boulter E, Burridge K (2011) The ‘invisible hand’: regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol 12:493–504PubMedPubMedCentralCrossRefGoogle Scholar
  302. 302.
    Benoit YD, Lussier C, Ducharme PA, Sivret S, Schnapp LM, Basora N et al (2009) Integrin alpha8beta1 regulates adhesion, migration and proliferation of human intestinal crypt cells via a predominant RhoA/ROCK-dependent mechanism. Biol Cell/ 101:695–708CrossRefGoogle Scholar
  303. 303.
    Hammar E, Tomas A, Bosco D, Halban PA (2009) Role of the Rho-ROCK (Rho-associated kinase) signaling pathway in the regulation of pancreatic beta-cell function. Endocrinology 150:2072–2079PubMedCrossRefGoogle Scholar
  304. 304.
    Bruewer M, Hopkins AM, Hobert ME, Nusrat A, Madara JL (2004) RhoA, Rac1, and Cdc42 exert distinct effects on epithelial barrier via selective structural and biochemical modulation of junctional proteins and F-actin. Am J Physiol Cell Physiol 287:C327–C335PubMedCrossRefGoogle Scholar
  305. 305.
    Chandhoke SK, Mooseker MS (2012) A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation. Mol Biol Cell 23:2468–2480PubMedPubMedCentralCrossRefGoogle Scholar
  306. 306.
    Terry SJ, Zihni C, Elbediwy A, Vitiello E, Leefa Chong San IV, Balda MS et al (2011) Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis. Nat Cell Biol 13:159–166PubMedPubMedCentralCrossRefGoogle Scholar
  307. 307.
    Babbin BA, Jesaitis AJ, Ivanov AI, Kelly D, Laukoetter M, Nava P et al (2007) Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. J Immunol 179:8112–8121PubMedCrossRefGoogle Scholar
  308. 308.
    Espejo R, Rengifo-Cam W, Schaller MD, Evers BM, Sastry SK (2010) PTP-PEST controls motility, adherens junction assembly, and Rho GTPase activity in colon cancer cells. Am J Physiol Cell Physiol 299:C454–C463PubMedPubMedCentralCrossRefGoogle Scholar
  309. 309.
    Chen P, Kartha S, Bissonnette M, Hart J, Toback FG (2012) AMP-18 facilitates assembly and stabilization of tight junctions to protect the colonic mucosal barrier. Inflamm Bowel Dis 18:1749–1759PubMedPubMedCentralCrossRefGoogle Scholar
  310. 310.
    Elbediwy A, Zihni C, Terry SJ, Clark P, Matter K, Balda MS (2012) Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex. J Cell Biol 198:677–693PubMedPubMedCentralCrossRefGoogle Scholar
  311. 311.
    Hopkins AM, Walsh SV, Verkade P, Boquet P, Nusrat A (2003) Constitutive activation of Rho proteins by CNF-1 influences tight junction structure and epithelial barrier function. J Cell Sci 116:725–742PubMedCrossRefGoogle Scholar
  312. 312.
    Sakamori R, Das S, Yu S, Feng S, Stypulkowski E, Guan Y et al (2012) Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice. J Clin Investig 122:1052–1065PubMedPubMedCentralCrossRefGoogle Scholar
  313. 313.
    Melendez J, Liu M, Sampson L, Akunuru S, Han X, Vallance J et al (2013) Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice. Gastroenterology 145:808–819PubMedCrossRefGoogle Scholar
  314. 314.
    Stappenbeck TS, Gordon JI (2000) Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine. Development 127:2629–2642PubMedGoogle Scholar
  315. 315.
    Myant KB, Scopelliti A, Haque S, Vidal M, Sansom OJ, Cordero JB (2013) Rac1 drives intestinal stem cell proliferation and regeneration. Cell Cycle 12:2973–2977PubMedPubMedCentralCrossRefGoogle Scholar
  316. 316.
    Segain JP, Raingeard de la Bletiere D, Sauzeau V, Bourreille A, Hilaret G, Cario-Toumaniantz C et al (2003) Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn’s disease and experimental colitis. Gastroenterology 124:1180–1187PubMedCrossRefGoogle Scholar
  317. 317.
    Lopez-Posadas R, Becker C, Gunther C, Tenzer S, Amann K, Billmeier U et al (2016) Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. J Clin Investig 126:611–626PubMedPubMedCentralCrossRefGoogle Scholar
  318. 318.
    Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687PubMedCrossRefGoogle Scholar
  319. 319.
    Sakamori R, Yu S, Zhang X, Hoffman A, Sun J, Das S et al (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480–5492PubMedPubMedCentralCrossRefGoogle Scholar
  320. 320.
    Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB et al (2013) ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12:761–773PubMedPubMedCentralCrossRefGoogle Scholar
  321. 321.
    Ray RM, Vaidya RJ, Johnson LR (2007) MEK/ERK regulates adherens junctions and migration through Rac1. Cell Motil Cytoskelet 64:143–156CrossRefGoogle Scholar
  322. 322.
    Olofsson B (1999) Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal 11:545–554PubMedCrossRefGoogle Scholar
  323. 323.
    Xiao H, Qin X, Ping D, Zuo K (2013) Inhibition of Rho and Rac geranylgeranylation by atorvastatin is critical for preservation of endothelial junction integrity. PLoS One 8:e59233PubMedPubMedCentralCrossRefGoogle Scholar
  324. 324.
    Pechlivanis M, Kuhlmann J (2006) Hydrophobic modifications of Ras proteins by isoprenoid groups and fatty acids—more than just membrane anchoring. Biochim Biophys Acta 1764:1914–1931PubMedCrossRefGoogle Scholar
  325. 325.
    Shen WP, Aldrich TH, Venta-Perez G, Franza BR Jr, Furth ME (1987) Expression of normal and mutant ras proteins in human acute leukemia. Oncogene 1:157–165PubMedGoogle Scholar
  326. 326.
    Lu J, Chan L, Fiji HD, Dahl R, Kwon O, Tamanoi F (2009) In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol Cancer Ther 8:1218–1226PubMedPubMedCentralCrossRefGoogle Scholar
  327. 327.
    Sebti SM, Hamilton AD (2000) Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues. Expert Opin Investig Drugs 9:2767–2782PubMedCrossRefGoogle Scholar
  328. 328.
    Rao PV, Peterson YK, Inoue T, Casey PJ (2008) Effects of pharmacologic inhibition of protein geranylgeranyltransferase type I on aqueous humor outflow through the trabecular meshwork. Invest Ophthalmol Vis Sci 49:2464–2471PubMedCrossRefGoogle Scholar
  329. 329.
    Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J et al (1995) Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem 270:26802–26806PubMedCrossRefGoogle Scholar
  330. 330.
    Blanco-Colio LM, Villa A, Ortego M, Hernandez-Presa MA, Pascual A, Plaza JJ et al (2002) 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 161:17–26PubMedCrossRefGoogle Scholar
  331. 331.
    Park HJ, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB (2002) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ Res 91:143–150PubMedCrossRefGoogle Scholar
  332. 332.
    Abe Y, Murano M, Murano N, Morita E, Inoue T, Kawakami K et al (2012) Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis. Dig Dis Sci 57:335–344PubMedCrossRefGoogle Scholar
  333. 333.
    Lee JY, Kim JS, Kim JM, Kim N, Jung HC, Song IS (2007) Simvastatin inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. Int Immunopharmacol 7:241–248PubMedCrossRefGoogle Scholar
  334. 334.
    Ikeda M, Takeshima F, Isomoto H, Shikuwa S, Mizuta Y, Ozono Y et al (2008) Simvastatin attenuates trinitrobenzene sulfonic acid-induced colitis, but not oxazalone-induced colitis. Dig Dis Sci 53:1869–1875PubMedCrossRefGoogle Scholar
  335. 335.
    Ballester I, Daddaoua A, Lopez-Posadas R, Nieto A, Suarez MD, Zarzuelo A et al (2007) The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid-induced colitis in rats. Br J Pharmacol 151:206–215PubMedPubMedCentralCrossRefGoogle Scholar
  336. 336.
    Sassa S, Okabe H, Nemoto N, Kikuchi H, Kudo H, Sakamoto S (2009) Ibadronate may prevent colorectal carcinogenesis in mice with ulcerative colitis. Anticancer Res 29:4615–4619PubMedGoogle Scholar

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© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Department of Medicine 1Friedrich-Alexander-University Erlangen-NurembergErlangenGermany

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