Cell and Tissue Research

, Volume 351, Issue 2, pp 269–280 | Cite as

Proteases and the gut barrier

  • Paolo Biancheri
  • Antonio Di Sabatino
  • Gino R. Corazza
  • Thomas T. MacDonald


Serine proteases, cysteine proteases, aspartic proteases and matrix metalloproteinases play an essential role in extracellular matrix remodeling and turnover through their proteolytic action on collagens, proteoglycans, fibronectin, elastin and laminin. Proteases can also act on chemokines, receptors and anti-microbial peptides, often potentiating their activity. The intestinal mucosa is the largest interface between the external environment and the tissues of the human body and is constantly exposed to proteolytic enzymes from many sources, including bacteria in the intestinal lumen, fibroblasts and immune cells in the lamina propria and enterocytes. Controlled proteolytic activity is crucial for the maintenance of gut immune homeostasis, for normal tissue turnover and for the integrity of the gut barrier. However, in intestinal immune-mediated disorders, pro-inflammatory cytokines induce the up-regulation of proteases, which become the end-stage effectors of mucosal damage by destroying the epithelium and basement membrane integrity and degrading the extracellular matrix of the lamina propria to produce ulcers. Protease-mediated barrier disruption in turn results in increased amounts of antigen crossing into the lamina propria, driving further immune responses and sustaining the inflammatory process.


Epithelial cell Extracellular matrix Inflammatory bowel disease Mucosal immunology Tumor necrosis factor-alpha 



A disintegrin and a metalloproteinase








Inflammatory bowel disease


Matrix metalloproteinase


Transmembrane domain


Transforming growth factor


T helper cell type


Tissue inhibitor of metalloproteinases


Toll-like receptor


Tumor necrosis factor


  1. Al-Sadi R, Ye D, Dokladny K, Ma TY (2008) Mechanism of IL-1beta-induced increase in intestinal epithelial tight junction permeability. J Immunol 180:5653–5661PubMedGoogle Scholar
  2. Arihiro S, Ohtani H, Hiwatashi N, Torii A, Sorsa T, Nagura H (2001) Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease. Histopathology 39:50–59PubMedCrossRefGoogle Scholar
  3. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14:275–281PubMedCrossRefGoogle Scholar
  4. Azghani AO, Gray LD, Johnson AR (1993) A bacterial protease perturbs the paracellular barrier function of transporting epithelial monolayers in culture. Infect Immun 61:2681–2686PubMedGoogle Scholar
  5. Babbin BA, Sasaki M, Gerner-Schmidt KW, Nusrat A, Klapproth JM (2009) The bacterial virulence factor lymphostatin compromises intestinal epithelial barrier function by modulating rho GTPases. Am J Pathol 174:1347–1357PubMedCrossRefGoogle Scholar
  6. Bamba S, Andoh A, Yasui H, Araki Y, Bamba T, Fujiyama Y (2003) Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17. J Gastroenterol 38:548–554PubMedGoogle Scholar
  7. Barnes MJ, Powrie F (2009) Regulatory T cells reinforce intestinal homeostasis. Immunity 31:401–411PubMedCrossRefGoogle Scholar
  8. Baugh MD, Perry MJ, Hollander AP, Davies DR, Cross SS, Lobo AJ, Taylor CJ, Evans GS (1999) Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117:814–822PubMedCrossRefGoogle Scholar
  9. Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9:356–368PubMedCrossRefGoogle Scholar
  10. Blaschitz C, Raffatellu M (2010) Th17 cytokines and the gut mucosal barrier. J Clin Immunol 30:196–203PubMedCrossRefGoogle Scholar
  11. Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, Heel DA van, Ruschendorf F, Toynbee M, Walne A, O’Toole EA, Martin JE, Lindley K, Vulliamy T, Abrams DJ, MacDonald TT, Harper JI, Kelsell DP (2011) Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 365:1502–1508PubMedCrossRefGoogle Scholar
  12. Brynskov J, Foegh P, Pedersen G, Ellervik C, Kirkegaard T, Bingham A, Saermark T (2002) Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut 51:37–43PubMedCrossRefGoogle Scholar
  13. Castaneda FE, Walia B, Vijay-Kumar M, Patel NR, Roser S, Kolachala VL, Rojas M, Wang L, Oprea G, Garg P, Gewirtz AT, Roman J, Merlin D, Sitaraman SV (2005) Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 129:1991–2008PubMedCrossRefGoogle Scholar
  14. Cesaro A, Abakar-Mahamat A, Brest P, Lassalle S, Selva E, Filippi J, Hébuterne X, Hugot JP, Doglio A, Galland F, Naquet P, Vouret-Craviari V, Mograbi B, Hofman PM (2009) Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 296:G1332–G1343PubMedCrossRefGoogle Scholar
  15. Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R (2002) Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 99:14338–14343PubMedCrossRefGoogle Scholar
  16. Ciccocioppo R, Di Sabatino A, Bauer M, Della Riccia DN, Bizzini F, Biagi F, Cifone MG, Corazza GR, Schuppan D (2005) Matrix metalloproteinase pattern in celiac duodenal mucosa. Lab Invest 85:397–407PubMedCrossRefGoogle Scholar
  17. Colón AL, Menchén LA, Hurtado O, De Cristóbal J, Lizasoain I, Leza JC, Lorenzo P, Moro MA (2001) Implication of TNF-alpha convertase (TACE/ADAM17) in inducible nitric oxide synthase expression and inflammation in an experimental model of colitis. Cytokine 16:220–226PubMedCrossRefGoogle Scholar
  18. Daum S, Bauer U, Foss HD, Schuppan D, Stein H, Riecken EO, Ullrich R (1999) Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 44:17–25PubMedCrossRefGoogle Scholar
  19. Di Sabatino A, Corazza GR (2009) Coeliac disease. Lancet 373:1480–1493PubMedCrossRefGoogle Scholar
  20. Di Sabatino A, Pender SL, Jackson CL, Prothero JD, Gordon JN, Picariello L, Rovedatti L, Docena G, Monteleone G, Rampton DS, Tonelli F, Corazza GR, MacDonald TT (2007) Functional modulation of Crohn’s disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology 133:137–149PubMedCrossRefGoogle Scholar
  21. Di Sabatino A, Saarialho-Kere U, Buckley MG, Gordon JN, Biancheri P, Rovedatti L, Corazza GR, MacDonald TT, Pender SLF (2009) Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab. Eur J Gastroenterol Hepatol 21:1049–1055PubMedCrossRefGoogle Scholar
  22. Di Sabatino A, Biancheri P, Rovedatti L, Macdonald TT, Corazza GR (2011a) Recent advances in understanding ulcerative colitis. Intern Emerg Med (in press)Google Scholar
  23. Di Sabatino A, Rovedatti L, Vidali F, Macdonald TT, Corazza GR (2011b) Recent advances in understanding Crohn’s disease. Intern Emerg Med (in press)Google Scholar
  24. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Asp Med 29:258–289CrossRefGoogle Scholar
  25. Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, Nast CC, Lechago J, Xu R, Naiki Y, Soliman A, Arditi M, Abreu MT (2005) 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–G1065PubMedCrossRefGoogle Scholar
  26. Garg P, Rojas M, Ravi A, Bockbrader K, Epstein S, Vijay-Kumar M, Gewirtz AT, Merlin D, Sitaraman SV (2006) Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis: contrasting role of gelatinases in the pathogenesis of colitis. J Immunol 177:4103–4112PubMedGoogle Scholar
  27. Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 3:583–590PubMedCrossRefGoogle Scholar
  28. Gordon JN, Pickard KM, Di Sabatino A, Prothero JD, Pender SL, Goggin PM, MacDonald TT (2008) Matrix metalloproteinase-3 production by gut IgG plasma cells in chronic inflammatory bowel disease. Inflamm Bowel Dis 14:195–203PubMedCrossRefGoogle Scholar
  29. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129:550–564PubMedGoogle Scholar
  30. Heuschkel RB, MacDonald TT, Monteleone G, Bajaj-Elliott M, Smith JA, Pender SL (2000) Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease. Gut 47:57–62PubMedCrossRefGoogle Scholar
  31. Huxley-Jones J, Clarke TK, Beck C, Toubaris G, Robertson DL, Boot-Handford RP (2007) The evolution of the vertebrate metzincins; insights from Ciona intestinalis and Danio rerio. BMC Evol Biol 7:63PubMedCrossRefGoogle Scholar
  32. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, Fujikado N, Tanahashi Y, Akitsu A, Kotaki H, Sudo K, Nakae S, Sasakawa C, Iwakura Y (2009) Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30:108–119PubMedCrossRefGoogle Scholar
  33. Ismail AS, Behrendt CL, Hooper LV (2009) Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J Immunol 182:3047–3054PubMedCrossRefGoogle Scholar
  34. Ito A, Mukaiyama A, Itoh Y, Nagase H, Thogersen IB, Enghild JJ, Sasaguri Y, Mori Y (1997) Degradation of interleukin 1beta by matrix metalloproteinases. J Biol Chem 271:14657–14660Google Scholar
  35. Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621PubMedCrossRefGoogle Scholar
  36. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118:1001–1011PubMedCrossRefGoogle Scholar
  37. Kirkegaard T, Hansen A, Bruun E, Brynskov J (2004) Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn’s disease. Gut 53:701–709PubMedCrossRefGoogle Scholar
  38. Li CK, Pender SL, Pickard KM, Chance V, Holloway JA, Huett A, Gonçalves NS, Mudgett JS, Dougan G, Frankel G, MacDonald TT (2004) Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice. J Immunol 173:5171–5179PubMedGoogle Scholar
  39. Lionetti P, Breese E, Braegger CP, Murch SH, Taylor J, MacDonald TT (1993) T-cell activation can induce either mucosal destruction or adaptation in cultured human fetal small intestine. Gastroenterology 105:373–381PubMedGoogle Scholar
  40. López-Boado YS, Wilson CL, Hooper LV, Gordon JI, Hultgren SJ, Parks WC (2000) Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J Cell Biol 148:1305–1315PubMedCrossRefGoogle Scholar
  41. Lottaz D, Buri C, Monteleone G, Rösmann S, Macdonald TT, Sanderson IR, Sterchi EE (2007) Compartmentalised expression of meprin in small intestinal mucosa: enhanced expression in lamina propria in coeliac disease. Biol Chem 388:337–341PubMedCrossRefGoogle Scholar
  42. MacDonald TT, Pender SL (2004) Mechanisms of tissue injury. In: Sartor RB, Sandborn WJ (eds) Kirsner’s inflammatory bowel diseases. Saunders, Edinburgh, pp 163–178Google Scholar
  43. Macpherson AJ, Geuking MB, McCoy KD (2005) Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 115:153–162PubMedCrossRefGoogle Scholar
  44. Matsuno K, Adachi Y, Yamamoto H, Goto A, Arimura Y, Endo T, Itoh F, Imai K (2003) The expression of matrix metalloproteinase matrilysin indicates the degree of inflammation in ulcerative colitis. J Gastroenterol 38:348–354PubMedCrossRefGoogle Scholar
  45. Maynard CL, Weaver CT (2009) Intestinal effector T cells in health and disease. Immunity 31:389–400PubMedCrossRefGoogle Scholar
  46. Menzel K, Hausmann M, Obermeier F, Schreiter K, Dunger N, Bataille F, Falk W, Scholmerich J, Herfarth H, Rogler G (2006) Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition in vivo. Clin Exp Immunol 146:169–180PubMedCrossRefGoogle Scholar
  47. Mohan R, Chintala SK, Jung JC, Villar WV, McCabe F, Russo LA, Lee Y, McCarthy BE, Wollenberg KR, Jester JV, Wang M, Welgus HG, Shipley JM, Senior RM, Fini ME (2002) Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem 277:2065–2072PubMedCrossRefGoogle Scholar
  48. Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, Fantini MC, Caprioli F, Tersigni R, Alessandroni L, MacDonald TT, Pallone F (2006) Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut 55:1774–1780PubMedCrossRefGoogle Scholar
  49. Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio Blanco G, Caruso R, Tersigni R, Alessandroni L, Biancone L, Naccari GC, MacDonald TT, Pallone F (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastroenterology 128:687–694Google Scholar
  50. Moriez R, Salvador-Cartier C, Theodorou V, Fioramonti J, Eutamene H, Bueno L (2005) Myosin light chain kinase is involved in lipopolysaccharide-induced disruption of colonic epithelial barrier and bacterial translocation in rats. Am J Pathol 167:1071–1079PubMedCrossRefGoogle Scholar
  51. Mosnier JF, Jarry A, Bou-Hanna C, Denis MG, Merlin D, Laboisse CL (2006) ADAM15 upregulation and interaction with multiple binding partners in inflammatory bowel disease. Lab Invest 86:1064–1073PubMedCrossRefGoogle Scholar
  52. Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ (1993) Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet 341:711–714PubMedCrossRefGoogle Scholar
  53. Noë V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114:111–118PubMedGoogle Scholar
  54. Parks WC (1999) Matrix metalloproteinases in repair. Wound Repair Regen 7:423–432PubMedCrossRefGoogle Scholar
  55. Parks WC, Wilson CL, López-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629PubMedCrossRefGoogle Scholar
  56. Pender SL, Lionetti P, Murch SH, Wathan N, MacDonald TT (1996) Proteolytic degradation of intestinal mucosal extracellular matrix after lamina propria T cell activation. Gut 39:284–290PubMedCrossRefGoogle Scholar
  57. Pender SL, MacDonald TT (2004) Matrix metalloproteinases and the gut—new roles for old enzymes. Curr Opin Pharmacol 4:546–550PubMedCrossRefGoogle Scholar
  58. Pender SL, Salmela MT, Monteleone G, Schnapp D, McKenzie C, Spencer J, Fong S, Saarialho-Kere U, MacDonald TT (2000) Ligation of alpha4ss1 integrin on human intestinal mucosal mesenchymal cells selectively up-regulates membrane type-1 matrix metalloproteinase and confers a migratory phenotype. Am J Pathol 157:1955–1962PubMedCrossRefGoogle Scholar
  59. Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT (1997) A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 158:1582–1590PubMedGoogle Scholar
  60. Pickard JM, Chervonsky AV (2010) Sampling of the intestinal microbiota by epithelial M cells. Curr Gastroenterol Rep 12:331–339PubMedCrossRefGoogle Scholar
  61. Pirilä E, Ramamurthy NS, Sorsa T, Salo T, Hietanen J, Maisi P (2003) Gelatinase A (MMP-2), collagenase-2 (MMP-8), and laminin-5 gamma2-chain expression in murine inflammatory bowel disease (ulcerative colitis). Dig Dis Sci 48:93–98PubMedCrossRefGoogle Scholar
  62. Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM (1999) The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 9:1441–1447PubMedCrossRefGoogle Scholar
  63. Prasad S, Mingrino R, Kaukinen K, Hayes KL, Powell RM, MacDonald TT, Collins JE (2005) Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Invest 85:1139–1162PubMedCrossRefGoogle Scholar
  64. Pruteanu M, Hyland NP, Clarke DJ, Kiely B, Shanahan F (2011) Degradation of the extracellular matrix components by bacterial-derived metalloproteases: implications for inflammatory bowel diseases. Inflamm Bowel Dis 17:1189–1200PubMedCrossRefGoogle Scholar
  65. Raffatellu M, George MD, Akiyama Y, Hornsby MJ, Nuccio SP, Paixao TA, Butler BP, Chu H, Santos RL, Berger T, Mak TW, Tsolis RM, Bevins CL, Solnick JV, Dandekar S, Bäumler AJ (2009) Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5:476–486PubMedCrossRefGoogle Scholar
  66. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, Kolls JK, Dandekar S, Bäumler AJ (2008) Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14:421–428PubMedCrossRefGoogle Scholar
  67. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241PubMedCrossRefGoogle Scholar
  68. Ravi A, Garg P, Sitaraman SV (2007) Matrix metalloproteinases in inflammatory bowel disease: boon or a bane? Inflamm Bowel Dis 13:97–107PubMedCrossRefGoogle Scholar
  69. Rescigno M (2011) The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol 32:256–264PubMedCrossRefGoogle Scholar
  70. Rescigno M, Di Sabatino A (2009) Dendritic cells in intestinal homeostasis and disease. J Clin Invest 119:2441–2450PubMedCrossRefGoogle Scholar
  71. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2:361–367PubMedCrossRefGoogle Scholar
  72. Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles CH, Rampton DS, Corazza GR, Monteleone G, Di Sabatino A, Macdonald TT (2009) Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut 58:1629–1636PubMedCrossRefGoogle Scholar
  73. Saarialho-Kere UK, Vaalamo M, Puolakkainen P, Airola K, Parks WC, Karjalainen-Lindsberg ML (1996) Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am J Pathol 148:519–526PubMedGoogle Scholar
  74. Salmela MT, MacDonald TT, Black D, Irvine B, Zhuma T, Saarialho-Kere U, Pender SL (2002) Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation. Gut 51:540–547PubMedCrossRefGoogle Scholar
  75. Salmela MT, Pender SL, Karjalainen-Lindsberg ML, Puolakkainen P, Macdonald TT, Saarialho-Kere U (2004) Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing. Scand J Gastroenterol 39:1095–1104PubMedCrossRefGoogle Scholar
  76. Salmela MT, Pender SL, Reunala T, MacDonald T, Saarialho-Kere U (2001) Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis. Gut 48:496–502PubMedCrossRefGoogle Scholar
  77. Sansonetti PJ (2004) War and peace at mucosal surfaces. Nat Rev Immunol 4:953–964PubMedCrossRefGoogle Scholar
  78. Scheller J, Chalaris A, Garbers C, Rose-John S (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32:380–387PubMedCrossRefGoogle Scholar
  79. Schönbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161:3340–3346PubMedGoogle Scholar
  80. Sengupta N, MacDonald TT (2007) The role of matrix metalloproteinases in stromal/epithelial interactions in the gut. Physiology (Bethesda) 22:401–409Google Scholar
  81. Shames SR, Bhavsar AP, Croxen MA, Law RJ, Mak SH, Deng W, Li Y, Bidshari R, Hoog CL de, Foster LJ, Finlay BB (2011) The pathogenic Escherichia coli type III secreted protease NleC degrades the host acetyltransferase p300. Cell Microbiol 13:1542–1557PubMedCrossRefGoogle Scholar
  82. Smith PD, Smythies LE, Shen R, Greenwell-Wild T, Gliozzi M, Wahl SM (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4:31–42PubMedCrossRefGoogle Scholar
  83. Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10:712–723PubMedCrossRefGoogle Scholar
  84. Steck N, Hoffmann M, Sava IG, Kim SC, Hahne H, Tonkonogy SL, Mair K, Krueger D, Pruteanu M, Shanahan F, Vogelmann R, Schemann M, Kuster B, Sartor RB, Haller D (2011a) Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology 141:959–971PubMedCrossRefGoogle Scholar
  85. Steck N, Mueller K, Schemann M, Haller D (2011b) Bacterial proteases in IBD and IBS. Gut (in press)Google Scholar
  86. Su L, Shen L, Clayburgh DR, Nalle SC, Sullivan EA, Meddings JB, Abraham C, Turner JR (2009) Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology 136:551–563PubMedCrossRefGoogle Scholar
  87. Turner JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9:799–809PubMedCrossRefGoogle Scholar
  88. Vaalamo M, Karjalainen-Lindsberg ML, Puolakkainen P, Kere J, Saarialho-Kere U (1998) Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol 152:1005–1014PubMedGoogle Scholar
  89. Vazeille E, Bringer MA, Gardarin A, Chambon C, Becker-Pauly C, Pender SL, Jakob C, Müller S, Lottaz D, Darfeuille-Michaud A (2011) Role of meprins to protect ileal mucosa of Crohn’s disease patients from colonization by adherent-invasive E. coli. PLoS One 6:e21199PubMedCrossRefGoogle Scholar
  90. Vijay-Kumar M, Sanders CJ, Taylor RT, Kumar A, Aitken JD, Sitaraman SV, Neish AS, Uematsu S, Akira S, Williams IR, Gewirtz AT (2007) Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest 117:3909–3921PubMedGoogle Scholar
  91. Villadangos JA, Bryant RA, Deussing J, Driessen C, Lennon-Duménil AM, Riese RJ, Roth W, Saftig P, Shi GP, Chapman HA, Peters C, Ploegh HL (1999) Proteases involved in MHC class II antigen presentation. Immunol Rev 172:109–120PubMedCrossRefGoogle Scholar
  92. von Lampe B, Barthel B, Coupland SE, Riecken EO, Rosewicz S (2000) Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47:63–73CrossRefGoogle Scholar
  93. 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 166:409–419PubMedCrossRefGoogle Scholar
  94. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, López-Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286:113–117PubMedCrossRefGoogle Scholar
  95. Wu S, Rhee KJ, Zhang M, Franco A, Sears CL (2007) Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage. J Cell Sci 120:1944–1952PubMedCrossRefGoogle Scholar
  96. Wu Z, Nybom P, Magnusson KE (2000) Distinct effects of Vibrio cholera haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell Microbiol 2:11–17PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Paolo Biancheri
    • 1
    • 2
    • 3
  • Antonio Di Sabatino
    • 1
  • Gino R. Corazza
    • 1
  • Thomas T. MacDonald
    • 2
  1. 1.First Department of Medicine, Fondazione IRCCS Policlinico S. MatteoUniversity of PaviaPaviaItaly
  2. 2.Centre for Immunology and Infectious Disease, Blizard InstituteBarts and the London School of Medicine and DentistryLondonUK
  3. 3.First Department of MedicineFondazione IRCCS Policlinico S. Matteo, University of PaviaPaviaItaly

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