Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: Living life on the edge of the wall

American Journal of Pathology

Volumn 173, Issue 5, 2008, Pages 1243-1252

  Fasano, Alessio ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACICLOVIR; ANTICONVULSIVE AGENT; CYCLOSPORIN A; CYTOPLASM PROTEIN; DOXORUBICIN; ENAMINONE; ENTEROTOXIN; GLIADIN; IMMUNOLOGICAL ADJUVANT; INSULIN; INULIN; MACROGOL 4000; MANNITOL; MEMBRANE PROTEIN; OVALBUMIN; PACLITAXEL; PROTEINASE INHIBITOR; SAQUINAVIR; SERINE PROTEINASE; SUCROSE; UNCLASSIFIED DRUG; ZONULA OCCLUDENS TOXIN; ZONULIN;

ADAPTIVE IMMUNITY; ADJUVANT THERAPY; AUTOIMMUNE DISEASE; AUTOIMMUNITY; BYSTANDER EFFECT; CELL JUNCTION; COMBINATION CHEMOTHERAPY; DIABETES MELLITUS; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DOSE INCREASE; GASTROINTESTINAL ABSORPTION; GASTROINTESTINAL MUCOSA; GASTROINTESTINAL TRACT; GENETIC SUSCEPTIBILITY; HIGH RISK POPULATION; HOMEOSTASIS; HUMAN; IMMUNE SYSTEM; IMMUNITY; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOGENESIS; INNATE IMMUNITY; INSULIN BLOOD LEVEL; INTESTINE LYMPHATIC TISSUE; INTESTINE MUCOSA; INTESTINE MUCOSA PERMEABILITY; LYMPHOID TISSUE; MACROMOLECULE; MEMBRANE TRANSPORT; MODULATION; MOLECULAR MIMICRY; MONOTHERAPY; NONHUMAN; PERMEABILITY BARRIER; PRIORITY JOURNAL; REVIEW; TIGHT JUNCTION; UPREGULATION;

EID: 55349143531     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.2353/ajpath.2008.080192     Document Type: Article

References (77)

1. Turner JR: Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application. Am J Pathol 2006, 169:1901-1909
2. Nusrat A, Turner JR, Madara JL: Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells. Am J Physiol 2000, 279:G851-G857
3. Furuse M, Hirase M, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S: Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 1993, 123:1777-1788
4. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S: Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 1998, 141:1539-1550
5. Martin-Padura I, Lostgalio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Vill A, Simmons D, Dejana E: Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998, 142:117-127
6. Ebnet K, Suzuki A, Ohno S, Vestweber D: Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 2004, 117:19-29
7. Anderson JM, Van Itallie CM: Tight junctions and the molecular basis for regulation of paracellular permeability. Am J Physiol 1995, 269:G467-G475
8. Mitic LL, Anderson JM: Molecular architecture of tight junctions. Annu Rev Physiol 1998, 60:121-142
9. Mitic LL, Van Itallie: Occludin and claudins: transmembrane proteins of the tight junction. Tight Junctions. Edited by Cereijido M, Anderson JM. Boca Raton, CRC Press, Inc., 2001, pp 213-230
10. Hirabayashi S, Hata Yutaka: JAM family proteins: tight junction proteins that belong to the immunoglobulin superfamily. Tight Junctions. Edited by Gonzales-Mariscal L. New York, 2006, CRC Press, pp 43-63
11. Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, Williams IR, Koval M, Peatman E, Campbell JA, Dermody TS, Nusrat A, Parkos CA: JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med 2007, 204:3067-3076
12. Citi S: The cytoplasmic plaque proteins of the tight junction. Tight Junctions. Edited by Cereijido M, Anderson JM. Boca Raton, CRC Press, Inc., 2001, pp 231-264
13. Zahraoui A, Joberty G, Arpin M, Fontaine JJ, Hellio R, Tavitian A, Louvard D: A small rab GTPase is distributed in cytoplasmic vesicles in non polarized cells but colocalized with the tight junction marker Zo-1 in polarized epithelial cells. J Cell Biol 1994, 124:101-115
14. Denker BM, Saha C, Khawaja S, Nigam SK: Involvement of a heterotrimeric G protein alpha subunit in tight junction biogenesis. J Biol Chem 1996, 271:25750-25753
15. Dodane V, Kachar B: Identification of isoforms of G proteins and PKC that colocalize with tight junctions. J Membr Biol 1996, 149:199-209
16. Keon BH, Schafer S, Kuhn C, Grund C, WW Franke: Symplekin, a novel type of tight junction plaque protein. J Cell Biol 1996, 134:1003-1018
17. Citi S, Sabannay H, Jakes R, Geiger B, Kendrich-Jones J: Cingulin, a new peripheral component of tight junctions. Nature 1988, 333:272-275
18. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC: Structure of the human class-I histocompatibility antigen, Hla-A2. Nature 1987, 329:506-512
19. Cuvelier C, Barbatis C, Mielants H, Devos M, Roels H, Veys E: Histopathology of intestinal inflammation related to reactive arthritis. Gut 1987, 28:394-401
20. Alpan O, Bachelder E, Isil E, Arnheiter H, Matzinger P: 'Educated' dendritic cells act as messengers from memory to naive T helper cells. Nat Immunol 2004, 5:615-622
21. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R: Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 2004, 118:229-241
22. Cario E, Gerken G, Podolsky DK: Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 2004, 127:224-238
23. Rumio C, Besusso D, Palazzo M, Selleri S, Sfondrini L, Dubini F, Menard S, Balsari A: Degranulation of Paneth cells via Toll-like receptor 9. Am J Pathol 2004, 165:373-381
24. Otte JM, Cario E, Podolsky DK: Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 2004, 126:1054-1070
25. Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, Lee HK, Shen C, Cojocaru G, Shenouda S, Kagnoff M, Eckmann L, Ben-Neriah Y, Raz E: Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 2006, 8:1327-1336
26. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004, 4:499-511
27. Pasare C, Medzhitov R: Toll-dependent control mechanisms of CD4 T cell activation. Immunity 2004, 21:733-741
28. Bashir ME, Louie S, Shi HN, Nagler-Anderson C: Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J Immunol 2004, 172:6978-6987
29. Fasano A, Baudry B, Pumplin DW, Wasserman SS, Tall BD, Ketley J, Kaper JB: Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 1991, 88:5242-5246
30. Fasano A, Fiorentini C, Donelli G, Uzzau S, Kaper JB, Margaretten K, Ding X, Guandalini S, Comstock L, Goldblum SE: Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest 1995, 96:710-720
31. Fasano A, Uzzau S, Fiore C, Margaretten K: The enterotoxic effect of zonula occludens toxin (Zot) on rabbit small intestine involves the paracellular pathway. Gastroenterology 1997, 112:839-846
32. Marcial MA, Carlson SL, Madara JL: Partitioning of paracellular conductance along the ileal crypt-villus axis: a hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships. J Membr Biol 1984, 80:59-70
33. Uzzau S, Lu R, Wang W, Fiore C, Fasano A: Purification and preliminary characterization of the zonula occludens toxin receptor from human (CaCo2) and murine (IEC6) intestinal cell lines. FEMS Microbiol Lett 2001, 194:1-5
34. Wang W, Uzzau S, Goldblum SE, Fasano A: Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 2000, 113:4435-4440
35. Baudry B, Fasano A, Ketley JM, Kaper JB: Cloning of a gene (zot) encoding a new toxin produced by Vibrio cholerae. Infect Immun 1992, 60:428-434
36. Di Pierro M, Lu R, Uzzau S, Wang W, Margaretten K, Pazzani C, Maimone F, Fasano A: Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem 2001, 276:19160-19165
37. El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, Catassi C, Fasano A: Host-dependent activation of the zonulin system is involved in the impairment of the gut barrier function following bacterial colonization. Gastroenterology 2002, 123:1607-1615
38. von Herrath MG, Fujinami RS, Whitton JL: Microorganisms and autoimmunity: making the barren field fertile? Nat Rev Microbiol 2003, 1:151-157
39. Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448:427-434
40. Fasano A, Shea-Donohue T: Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005, 2:416-422
41. Fasano A: Celiac disease - how to handle a clinical chameleon. N Engl J Med 2003, 348:2568-2570
42. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A: Gliadin induces an increase in intestinal permeability and intestinal zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008, 135:194-204
43. Fasano A: Pathological and therapeutic implications of macromolecule passage through the tight junction. Tight Junctions. Edited by Cereijido M, Anderson JM. Boca Raton, CRC Press, Inc., 2001, pp 697-722
44. Madara JL, Trier JS: Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Invest 1980, 43:254-261
45. Schulzke JD, Bentzel CJ, Schulzke I, Riecken EO, Fromm M: Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 1998, 43:435-441
46. Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE: Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 2000, 358:1518-1519
47. Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR, Drago S, Congia M, Fasano A: Early effects of gliadin on enterocyte intracellular signaling involved in intestinal barrier function. Gut 2003, 52:218-223
48. Nikulina M, Habich C, Flohé SB, Scott FW, Kolb H: Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol 2004, 173:1925-1933
49. Thomas KE, Sapone A, Fasano A, Vogel SN: Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are Myd88-dependent: role of the innate immune response in celiac disease. J Immunol 2006, 176:2512-2521
50. Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB: The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007, 26:757-766
51. Weber CR, Turner JR: Inflammatory bowel disease: is it really just another break in the wall? Gut 2007, 56:6-8
52. Wang F, Schwarz BT, Graham WV, Wang Y, Su L, Clayburgh DR, Abraham C, Turner JR: IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 2006, 131:1153-1163
53. Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR: 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 2005, 166:409-419
54. Ye D, Ma I, Ma TY: Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am J Physiol 2006, 290:G496-G504
55. Al-Sadi RM, Ma TY: IL-1beta causes an increase in intestinal epithelial tight junction permeability. J Immunol 2007, 178:4641-4649
56. Brandtzaeg P, Halstensen TS, Kett K, Krajci P, Kvale D, Rognum TO, Scott H, Sollid LM: Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989, 97:1562-1584
57. Brandtzaeg P: Overview of the mucosal immune system. Curr Top Microbiol Immunol 1989, 146:13-25
58. De Magistris L, Secondulfo M, Iafusco D, Carbone AG, Urio A, Pontoni G, Carratu R: Altered mannitol absorption in diabetic children. Ital J Gastroenterol 1996, 28:367
59. Carratu R, Secondulfo M, de Magistris L, Iafusco D, Urio A, Carbone MG, Pontoni G, Carteni M, Prisco F: Altered intestinal permeability to mannitol in diabetes mellitus type I. J Pediatr Gastroenterol Nutr 1999, 28:264-269
60. Secondulfo M, De Magistris L, Sapone A, Di Monda G, Esposito P, Carratu R: Intestinal permeability and diabetes mellitus type 2. Minerva Gastroenterol Dietol 1999, 45:187-192
61. Mooradian AD, Morley JE, Levine AS, Prigge WF, Gebhard RL: Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia 1986, 29:221-224
62. Cooper BT, Ukabam SO, O'Brien IA, Hare JP, Corrall RJ: Intestinal permeability in diabetic diarrhoea. Diabet Med 1987, 4:49-52
63. Meddings JB, Jarand J, Urbanski SJ, Hardin J, Gall DG: Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat. Am J Physiol 1999, 276:G951-G957
64. Watts T, Berti I, Sapone A, Gerarduzzi T, Not T, Zielke R, Fasano A: Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci USA 2005, 102:2916-2921
65. Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, Lampis R, Kryszak D, Cartenì M, Generoso M, Iafusco D, Prisco F, Laghi F, Riegler G, Carratu R, Counts D, Fasano A: Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 2006, 55:1443-1449
66. Kondoh M, Yagi K: Tight junction modulators: promising candidates for drug delivery. Curr Med Chem 2007, 14:2482-2488
67. Fasano A, Uzzau S: Modulation of intestinal tight junctions by zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J Clin Invest 1997, 99:1158-1164
68. Watts TL, Alexander T, Hansen B, Fasano A: Utilizing the paracellular pathway: a novel approach for the delivery of oral insulin in diabetic rhesus macaques. J Invest Med 2000, 48:185
69. Karyekar CS, Fasano A, Raje S, Lu R, Dowling TC, Eddington ND: Zonula occludens toxin increases the permeability of molecular weight markers and chemotherapeutic agents across the bovine brain microvessel endothelial cells. J Pharm Sci 2003, 92:414-423
70. Cox D, Gao H, Raje S, Scott KR, Eddington ND: Enhancing the permeation of marker compounds and enaminone anticonvulsants across Caco-2 monolayers by modulating tight junctions using zonula occludens toxin. Eur J Pharm Biopharm 2001, 52:145-150
71. Cox D, Raje S, Gao H, Salama NN, Eddington ND: Enhanced permeability of molecular weight markers and poorly bioavailable compounds across Caco-2 cell monolayers using the absorption enhancer, zonula occludens toxin. Pharm Res 2002, 19:1680-1688
72. Salama NN, Fasano A, Lu R, Eddington ND: Effect of the biologically active fragment of zonula occludens toxin, ΔG, on the intestinal paracellular transport and oral absorption of mannitol. Int J Pharm 2003, 251:113-121
73. Salama NN, Fasano A, Thakar M, Eddington ND: The effect of ΔG on the transport and oral absorption of macromolecules. J Pharm Sci 2004, 93:1310-1319
74. Salama NN, Fasano A, Thakar M, Eddington ND: The effect of ΔG on the oral bioavailability of low bioavailable therapeutic agents. J Pharmacol Exp Ther 2005, 312:199-205
75. Rossi M, Maurano F, Luongo D, Fasano A, Uzzau S, Auricchio S, Troncone R: Zonula occludens toxin (Zot) interferes with the induction of nasal tolerance to gliadin. Immunol Lett 2002, 81:217-221
76. Marinaro M, Di Tommaso A, Uzzau S, Fasano A, De Magistris MT: Zonula occludens toxin is a powerful mucosal adjuvant for intranasally delivered antigens. Infect Immun 1999, 67:1287-1291
77. Marinaro M, Fasano A, De Magistris MT: Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses. Infect Immun 2003, 71:1897-1902