Background/Aim: ZO-1 is a good marker for tight junction integrity which may be damaged in many intestinal diseases. ZO-1 can also accumulate in the cellular nucleus in addition to sites of cell-cell contact, suggesting a potential role in cellular proliferation and differentiation. We evaluated the expression and distribution of ZO-1 in patients with celiac disease before and after a gluten-free diet. Methods: The ZO-1 expression was evaluated semiquantitatively by means of immunohistochemical analysis in duodenal bioptic specimens of 10 consecutive patients with celiac disease before and after a gluten-free diet and in 10 controls. Furthermore, the nuclear staining was analyzed quantitatively, evaluating 3,000 cells for each count, and it was expressed as a percentage of labeled nuclei over the total of analyzed cells. Results: The intestinal mucosa of untreated celiac disease patients shows a globally lower ZO-1 labeling than that of controls. The expression of ZO-1 in the treated celiac mucosa did not differ significantly from normal intestinal mucosa of healthy subjects. At the crypt level of untreated celiac mucosa, a low intensity of nuclear labeling (1.75 ± 0.32%) was found, while in both treated celiac disease patients and in normal subjects we observed a statistically significant higher percentage of strongly labeled nuclei (53.72 ± 6.30% and 56.79 ± 5.45%, respectively; p = 0.0002). Conclusions: Our data show a global underexpression of ZO-1 in the duodenal mucosa of active celiac disease patients. Gluten withdrawal allows a normalization of the ZO-1 expression in treated celiac disease patients. Furthermore, the particular pattern of ZO-1 resembles the cellular distribution in undifferentiated cells and may be the result of immaturity of the enterocytes in untreated celiac sprue.

1.
Hollander D: The intestinal permeability barrier: A hypothesis as to its regulation and involvement in Crohn’s disease. Scand J Gastroenterol 1992;27:721–726.
[PubMed]
2.
Balda MS, Matter K: Tight junctions. J Cell Sci 1998;111:541–547.
[PubMed]
3.
Lapierre LA: The molecular structure of the tight junction. Adv Drug Deliv Rev 2000;41:255–264.
[PubMed]
4.
Marin ML, Greenstein AJ, Geller SA, Gordon RE, Afuses AH Jr: A freeze fracture study of Crohn’s disease of the terminal ileum: Changes in epithelial tight junction organization. Am J Gastroenterol 1983;78:537–547.
[PubMed]
5.
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(4 Pt 1):435–441.
6.
Caselli M, Ruina M, La Corte R, Trevisani L, Sartori S, Dentale A, Gaudenzi P, Trotta F, Alvisi V: Ultrastructural damage of gastric epithelium in patients taking NSAIDs. Ital J Gastroenterol 1996;28(suppl 4):16–18.
7.
Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA: Identification of ZO-1: A high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 1986;103:755–766.
[PubMed]
8.
Balda MS, Anderson JM: Two classes of tight junctions are revealed by ZO-1 isoforms. Am J Physiol 1993;264:C918–C924.
[PubMed]
9.
Tsukita S, Furuse M, Itoh M: Molecular dissection of tight junctions. Cell Struct Funct 1996;21:381–385.
[PubMed]
10.
Gasbarrini G, Montalto M: Structure and function of tight junctions: Role in intestinal barrier. Ital J Gastroenterol Hepatol 1999;31:481–488.
[PubMed]
11.
Madara JL, Carlson S, Anderson JM: ZO-1 mantains its spatial distribution but dissociates from junctional fibrils during tight junction regulation. Am J Physiol 1993;264:C1096-C1101.
[PubMed]
12.
Blum MS, Toninelli E, Anderson JM, Balda MS, Zhou J, O’Donnell L, Pardi R, Bender JR: Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines. Am J Physiol 1997;273(1 Pt 2):H286–H294.
13.
Jensen-Jarolim E, Gajdzik L, Haberl I, Kraft D, Scheiner O, Graf J: Hot spices influence permeability of human intestinal epithelial monolayers. J Nutr 1998;128:577–581.
[PubMed]
14.
Gottardi CJ, Arpin M, Fanning AS, Louvard D: The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts. Proc Natl Acad Sci USA 1996;93:10779–10784.
[PubMed]
15.
Madara JL, Stafford J, Barenberg D, Carlson S: Functional coupling of tight junctions and microfilaments in T84 monolayers. Am J Physiol 1988;254:G416–G423.
[PubMed]
16.
Itoh M, Nagafuchi A, Yonemura S, Kitani-Yasuda K, Tsukita S, Tsukita S: The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J Cell Biol 1993;121:491–502.
[PubMed]
17.
Madara JL, Dharmsathaphorn K: Occluding junction structure-function relationships in a cultured epithelial monolayer. J Cell Biol 1985;101:2124–2133.
[PubMed]
18.
Cereijido M, Shoshani L, Contreras RG: Molecular physiology and pathophysiology of tight junctions. I. Biogenesis of tight junctions and epithelial polarity. Am J Physiol Gastrointest Liver Physiol 2000;279:G477–G482.
[PubMed]
19.
Gumbiner B: Structure, biochemistry and assembly of epithelial tight junctions. Am J Physiol 1987;253:C749–C758.
[PubMed]
20.
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 Gastrointest Liver Physiol 2000;279:G851–G857.
[PubMed]
21.
Fasano A, Baudry B, Pumplin DW, Wasserman SS, Tall BD, Ketley JM, Kaper JB: Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 1991;88:5242–5246.
[PubMed]
22.
Smecuol E, Bai JC, Vasquez H, Kogan Z, Cabanne A, Niveloni S, Pedreira S, Boerr L, Maurino E, Meddings JB: Gastrointestinal permeability in celiac disease. Gastroenterology 1997;112:1129–1136.
[PubMed]
23.
Ma TY: Intestinal epithelial barrier dysfunction in Crohn’s disease. Proc Soc Exp Biol Med 1997;214:318–327.
[PubMed]
24.
Gardner TW, Lesher T, Khin S, Vu C, Barber AJ, Brennan WA: Histamine reduces ZO-1 tight junctional protein expression in cultured retinal microvascular endothelial cells. Biochem J 1996;320:717–721.
[PubMed]
25.
Philpott DJ, McKay DM, Sherman PM, Perdue MH: Infection of T84 cells with enteropathogenic Escherichia coli alters barrier and transport functions. Am J Physiol 1996;270(4 Pt 1):G634–G645.
26.
Sears CL: Molecular physiology and pathophysiology of tight junctions. V. Assault of the tight junction by enteric pathogens. Am J Physiol Gastrointest Liver Physiol 2000;279:G1129–G1134.
[PubMed]
27.
Wang W, Uzzau S, Goldblum SE, Fasano A: Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 2000;113(Pt 24):4435–4440.
28.
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;355:1518–1519.
[PubMed]
29.
Magliocca FM, Bonamico M, Petrozza V, Correr S, Montuori M, Triglione P, Carpino F: Scanning electron microscopy of the small intestine during gluten challenge in celiac disease. Arch Histol Cytol 1992;55(suppl):125–130.
30.
Gonzalez-Mariscal L, Betanzos A, Avila-Flores A: MAGUK proteins: Structure and role in the tight junction. Semin Cell Dev Biol 2000;11:315–324.
[PubMed]
31.
Hoover KB, Liao SY, Bryant PJ: Loss of the tight junction MAGUK ZO-1 in breast cancer: Relationship to glandular differentiation and loss of heterozygosity. Am J Pathol 1998;153:1767–1773.
[PubMed]
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.
[PubMed]
33.
Matter K, Balda MS: Biogenesis of tight junctions: The C-terminal domain of occludin mediates basolateral targeting. J Cell Sci 1998;111:511–519.
[PubMed]
34.
Moss SF, Attia L, Scholes JV, Walters JRF, Holt PR: Increased small intestinal apoptosis in coeliac disease. Gut 1996;39:811–817.
[PubMed]
35.
Sommers CL, Byers SW, Thompson EW, Torri JA, Gelmann EP: Differentiation state and invasiveness of human breast cancer cell lines. Breast Cancer Res Treat 1994;31:325–355.
[PubMed]
36.
Tsukita S, Itoh M, Yonemura S, Tsukita S: Submembranous junctional plaque proteins include potential tumor suppressor molecules. J Cell Biol 1993;123:1049–1053.
[PubMed]
37.
Karczewski J, Groot J: Molecular physiology and pathophysiology of tight junctions. III. Tight junction regulation by intracellular messengers: Differences in response within and between epithelia. Am J Physiol Gastrointest Liver Physiol 2000;279:G660–G665.
[PubMed]
You do not currently have access to this content.