Digestive Diseases and Sciences

, Volume 57, Issue 7, pp 1813–1821 | Cite as

Bin1 Attenuation Suppresses Experimental Colitis by Enforcing Intestinal Barrier Function

  • Mee Young Chang
  • Janette Boulden
  • M. Carmen Valenzano
  • Alejandro P. Soler
  • Alexander J. Muller
  • James M. Mullin
  • George C. Prendergast
Original Article

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.

Keywords

IBD Colitis Inflammation Inflammatory cytokines Tight junctions Epithelial barrier 

Notes

Acknowledgments

We thank Gwen Guillard for tissue sectioning and histology. This work was supported in part by NCI R01 grants CA100123 and CA10954 with additional support from the Charlotte Geyer Foundation and the Lankenau Medical Center Foundation (G.C.P.). A.J.M. is the recipient of grants from the Lance Armstrong Foundation, the DoD Breast Cancer Research Program, and the State of Pennsylvania Department of Health (CURE/Tobacco Settlement Award). J.M.M is a recipient of a grant from the Sharpe-Strumia Foundation and the Prevent Cancer Foundation.

Conflict of interest

None.

Supplementary material

10620_2012_2147_MOESM1_ESM.pdf (64 kb)
Supplemental Figure 1. Effect of Bin1 loss on immune cytokine expression. Serum was collected from mice administered 3 % DSS in drinking water for 7 days and the level of the immune cytokines indicated was determined by a cytometric bead array. The data represent the determination of at least three data points per sample (PDF 63 kb)

References

  1. 1.
    Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118:671–674.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274.PubMedCrossRefGoogle Scholar
  4. 4.
    Hibi T, Ogata H, Sakuraba A. Animal models of inflammatory bowel disease. J Gastroenterol. 2002;37:409–417.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    Steinhoff U, Brinkmann V, Klemm U, et al. Autoimmune intestinal pathology induced by hsp60-specific cd8 t cells. Immunity. 1999;11:349–358.PubMedCrossRefGoogle Scholar
  9. 9.
    Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology. 1995;109:1344–1367.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 14.
    Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol. 1992;262:L647–L661.PubMedGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 16.
    Madara JL. Regulation of the movement of solutes across tight junctions. Annu Rev Physiol. 1998;60:143–159.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Cooper HS, Murthy SNS, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–248.PubMedGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Hawker PC, McKay JS, Turnberg LA. Electrolyte transport across colonic mucosa from patients with inflammatory bowel disease. Gastroenterology. 1980;79:508–511.PubMedGoogle Scholar
  30. 30.
    Hollander D. Crohn’s disease—a permeability disorder of the tight junction? Gut. 1988;29:1621–1624.PubMedCrossRefGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 32.
    Pohl C, Hombach A, Kruis W. Chronic inflammatory bowel disease and cancer. Hepatogastroenterology. 2000;47:57–70.PubMedGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.Google Scholar
  36. 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.Google Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Mee Young Chang
    • 1
  • Janette Boulden
    • 1
  • M. Carmen Valenzano
    • 1
  • Alejandro P. Soler
    • 1
    • 2
  • Alexander J. Muller
    • 1
  • James M. Mullin
    • 1
  • George C. Prendergast
    • 1
    • 3
  1. 1.Lankenau Institute for Medical ResearchWynnewoodUSA
  2. 2.Richfield Laboratory of DermatopathologyCincinnatiUSA
  3. 3.Department of Pathology, Anatomy & Cell Biology, Jefferson Medical College and Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations