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01.07.2012 | Original Article

Bin1 Attenuation Suppresses Experimental Colitis by Enforcing Intestinal Barrier Function

verfasst von: Mee Young Chang, Janette Boulden, M. Carmen Valenzano, Alejandro P. Soler, Alexander J. Muller, James M. Mullin, George C. Prendergast

Erschienen in: Digestive Diseases and Sciences | Ausgabe 7/2012

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Abstract

Background

Inflammatory bowel disease (IBD) is associated with defects in intestinal barriers that rely upon cellular tight junctions. Thus, identifying genes that could be targeted to enforce tight junctions and improve barrier function may lead to new treatment strategies for IBD.

Aims

This preclinical study aimed to evaluate an hypothesized role for the tumor suppressor gene Bin1 as a modifier of the severity of experimental colitis.

Methods

We ablated the Bin1 gene in a mosaic mouse model to evaluate its effects on experimental colitis and intestinal barrier function. Gross pathology, histology and inflammatory cytokine expression patterns were characterized and ex vivo physiology determinations were conducted to evaluate barrier function in intact colon tissue.

Results

Bin1 attenuation limited experimental colitis in a sexually dimorphic manner with stronger protection in female subjects. Colitis suppression was associated with an increase in basal transepithelial electrical resistance (TER) and a decrease in paracellular transepithelial flux, compared to control wild-type animals. In contrast, Bin1 attenuation did not affect short circuit current, nor did it alter the epithelial barrier response to non-inflammatory permeability enhancers in the absence of inflammatory stimuli.

Conclusions

Bin1 is a genetic modifier of experimental colitis that controls the paracellular pathway of transcellular ion transport regulated by cellular tight junctions. Our findings offer a preclinical validation of Bin1 as a novel therapeutic target for IBD treatment.

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Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118:671–674.PubMedCrossRef

Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75:253–261.PubMedCrossRef

Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274.PubMedCrossRef

Hibi T, Ogata H, Sakuraba A. Animal models of inflammatory bowel disease. J Gastroenterol. 2002;37:409–417.PubMedCrossRef

Cong Y, Brandwein SL, McCabe RP, et al. Cd4 + t cells reactive to enteric bacterial antigens in spontaneously colitic c3 h/hejbir mice: Increased t helper cell type 1 response and ability to transfer disease. J Exp Med. 1998;187:855–864.PubMedCrossRef

Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795–803.PubMed

Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98:694–702.PubMed

Steinhoff U, Brinkmann V, Klemm U, et al. Autoimmune intestinal pathology induced by hsp60-specific cd8 t cells. Immunity. 1999;11:349–358.PubMedCrossRef

Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology. 1995;109:1344–1367.PubMedCrossRef

10.

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.PubMedCrossRef

11.

Soderholm JD, Peterson KH, Olaison G, et al. Epithelial permeability to proteins in the noninflamed ileum of Crohn’s disease? Gastroenterology. 1999;117:65–72.PubMedCrossRef

12.

Schmitz H, Barmeyer C, Fromm M, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology. 1999;116:301–309.PubMedCrossRef

13.

Su L, Shen L, Clayburgh DR, et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2009;136:551–563.PubMedCrossRef

14.

Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol. 1992;262:L647–L661.PubMed

15.

Cano-Cebrian MJ, Zornoza T, Granero L, Polache A. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: A target for drug delivery. Curr Drug Deliv. 2005;2:9–22.PubMedCrossRef

16.

Madara JL. Regulation of the movement of solutes across tight junctions. Annu Rev Physiol. 1998;60:143–159.PubMedCrossRef

17.

Kitajima S, Takuma S, Morimoto M. Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium. Exp Anim. 1999;48:137–143.PubMedCrossRef

18.

Soderholm JD, Olaison G, Peterson KH, et al. Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn’s disease. Gut. 2002;50:307–313.PubMedCrossRef

19.

Prendergast GC, Muller AJ, Ramalingam A, Chang MY. Bar the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta. 2009;1795:25–36.PubMed

20.

Ren G, Vajjhala P, Lee JS, Winsor B, Munn AL. The bar domain proteins: molding membranes in fission, fusion, and phagy. Microbiol Mol Biol Rev. 2006;70:37–120.PubMedCrossRef

21.

Chang MY, Boulden J, Katz JB, et al. Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer Res. 2007;67:7605–7612.PubMedCrossRef

22.

DuHadaway JB, Lynch FJ, Brisbay S, et al. Immunohistochemical analysis of bin1/amphiphysin ii in human tissues: diverse sites of nuclear expression and losses in prostate cancer. J Cell Biochem. 2003;88:635–642.PubMedCrossRef

23.

Grelle G, Kostka S, Otto A, et al. Identification of vcp/p97, carboxyl terminus of hsp70-interacting protein (chip), and amphiphysin ii interaction partners using membrane-based human proteome arrays. Mol Cell Proteomics. 2006;5:234–244.PubMed

24.

Scott GN, DuHadaway J, Pigott E, et al. The immunoregulatory enzyme ido paradoxically drives b cell-mediated autoimmunity. J Immunol. 2009;182:7509–7517.PubMedCrossRef

25.

Mullin JM, Soler AP, Laughlin KV, et al. Chronic exposure of llc-pk1 epithelia to the phorbol ester tpa produces polyp-like foci with leaky tight junctions and altered protein kinase c-alpha expression and localization. Exp Cell Res. 1996;227:12–22.PubMedCrossRef

26.

Cooper HS, Murthy SNS, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–248.PubMed

27.

Madsen KL, Malfair D, Gray D, Doyle JS, Jewell LD, Fedorak RN. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis. 1999;5:262–270.PubMedCrossRef

28.

Mullin JM, Agostino N, Rendon-Huerta E, Thornton JJ. Keynote review: epithelial and endothelial barriers in human disease. Drug Discov Today. 2005;10:395–408.PubMedCrossRef

29.

Hawker PC, McKay JS, Turnberg LA. Electrolyte transport across colonic mucosa from patients with inflammatory bowel disease. Gastroenterology. 1980;79:508–511.PubMed

30.

Hollander D. Crohn’s disease—a permeability disorder of the tight junction? Gut. 1988;29:1621–1624.PubMedCrossRef

31.

Marin ML, Greenstein AJ, Geller SA, Gordon RE, Aufses 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

32.

Pohl C, Hombach A, Kruis W. Chronic inflammatory bowel disease and cancer. Hepatogastroenterology. 2000;47:57–70.PubMed

33.

Brant SR, Nguyen GC. Is there a gender difference in the prevalence of crohn’s disease or ulcerative colitis? Inflamm Bowel Dis. 2008;14:S2–S3.PubMedCrossRef

34.

Nelson RL, Dollear T, Freels S, Persky V. The relation of age, race, and gender to the subsite location of colorectal carcinoma. Cancer. 1997;80:193–197.PubMedCrossRef

35.

Ramalingam A, Wang X, Gabello M, et al. Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern. Am J Physiol Cell Physiol. 2010;299:C1028–1035.

36.

Roxas JL, Koutsouris A, Bellmeyer A, Tesfay S, Royan S, Falzari K, Harris A, Cheng H, Rhee KJ, Hecht G. Enterohemorrhagic E. coli alters murine intestinal epithelial tight junction protein expression and barrier function in a shiga toxin independent manner. Lab Invest. 2010;90:1152–1168.

37.

Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatory target of the tumor suppressor gene bin1, potentiates cancer chemotherapy. Nature Med. 2005;11:312–319.PubMedCrossRef

38.

Katz JB, Muller AJ, Metz R, Prendergast GC. Indoleamine 2,3-dioxygenase in t-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–221.PubMedCrossRef

39.

Prendergast GC, Metz R, Muller AJ. Towards a genetic definition of cancer-associated inflammation: Role of the ido pathway. Am J Pathol. 2010;176:2082–2087.PubMedCrossRef

40.

Ciorba MA, Bettonville EE, McDonald KG, et al. Induction of ido-1 by immunostimulatory DNA limits severity of experimental colitis. J Immunol. 2010;184:3907–3916.PubMedCrossRef

Titel: Bin1 Attenuation Suppresses Experimental Colitis by Enforcing Intestinal Barrier Function
verfasst von: Mee Young Chang
Janette Boulden
M. Carmen Valenzano
Alejandro P. Soler
Alexander J. Muller
James M. Mullin
George C. Prendergast
Publikationsdatum: 01.07.2012
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 7/2012
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-012-2147-y

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Abstract

Background

Aims

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