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Digestive Diseases and Sciences

, Volume 57, Issue 5, pp 1227–1237 | Cite as

The N-Terminal Fragment of Chromogranin A, Vasostatin-1 Protects Mice From Acute or Chronic Colitis Upon Oral Administration

  • Cristiano Rumio
  • Giuseppina F. Dusio
  • Barbara Colombo
  • Anna Gasparri
  • Diego Cardani
  • Fabrizio MarcucciEmail author
  • Angelo Corti
Original Article

Abstract

Background

Vasostatin-1 (VS-1), the N-terminal fragment of chromogranin A (CgA), decreases the permeability of endothelial cells in vitro and in vivo.

Aims

Here, we investigated whether a similar effect could be observed also on intestinal epithelial cells (IECs) in vitro and whether VS-1 could have favorable effects on animal models of acute or chronic colitis, which are characterized by increased permeability of the intestinal epithelium.

Methods

In vitro, VS-1 was tested on IEC monolayers showing increased permeability, on mechanically injured IEC monolayers, and on the production of the chemokine IL-8/KC by lipopolysaccharide (LPS)-stimulated IECs. In vivo, VS-1 was tested in animal models of dextran sodium salt (DSS)-induced acute or chronic colitis.

Results

In vitro, VS-1 inhibited increased permeability of IECs induced by interferon-γ and tumor necrosis factor-α. Moreover, VS-1 promoted healing of mechanically injured IEC monolayers, most likely through stimulation of cell migration, rather than cell proliferation. Eventually, VS-1 inhibited LPS-induced production of IL-8. In vivo, VS-1 exerted protective effects in animal models of acute or chronic colitis upon oral, but not systemic administration.

Conclusions

VS-1 is therapeutically active in animal models of acute or chronic, DSS-induced colitis. The mechanisms underlying this effect are likely to be multiple, and may include inhibition of enhanced intestinal permeability, repair of injured intestinal mucosae, and inhibition of the production of IL-8/KC and possibly other inflammatory cytokines.

Keywords

Chromogranin A Vasostatin-1 Intestinal epithelial cells Inflammatory bowel diseases 

Notes

Acknowledgment

This work was supported by the Associazione Italiana per la Ricerca sul Cancro.

Conflict of interest

None of the authors has any conflict of interest.

References

  1. 1.
    Podolsky D. Inflammatory bowel disease. N Engl J Med. 2007;347:417–429.CrossRefGoogle Scholar
  2. 2.
    Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55:1512–1520.PubMedCrossRefGoogle Scholar
  3. 3.
    Arrieta MC, Madsen K, Doyle J, Meddings J. Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut. 2009;58:41–48.PubMedCrossRefGoogle Scholar
  4. 4.
    D’Inca R, Di Leo V, Corrao G, et al. Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol. 1999;94:2956–2960.PubMedGoogle Scholar
  5. 5.
    Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986;105:883–885.PubMedGoogle Scholar
  6. 6.
    Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn’s disease in a subject with familial risk. Gastroenterology. 2000;119:1740–1744.PubMedCrossRefGoogle Scholar
  7. 7.
    May GR, Sutherland SR, Meddings JB. Is small intestinal permeability really increased in relatives of patients with Crohn’s disease? Gastroenterology. 1993;104:1627–1632.PubMedGoogle Scholar
  8. 8.
    Wyatt J, Vogelsang H, Hübl W, Waldhöer T, Lochs H. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet. 1993;341:1437–1439.PubMedCrossRefGoogle Scholar
  9. 9.
    Sartor RB. Role of commensal enteric bacteria in the pathogenesis of immune-mediated intestinal inflammation: lessons from animal models and implications for translational research. J Pediatr Gastroenterol Nutr. 2005;40:S30–S31.PubMedCrossRefGoogle Scholar
  10. 10.
    Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495–549.PubMedCrossRefGoogle Scholar
  11. 11.
    Strober W. Why study animal models of IBD? Inflamm Bowel Dis. 2008;14:S129–S131.PubMedCrossRefGoogle Scholar
  12. 12.
    Baert FJ, D’Haens GR, Peeters M, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology. 1999;116:22–28.PubMedCrossRefGoogle Scholar
  13. 13.
    D’haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterol. 1999;116:1029–1034.CrossRefGoogle Scholar
  14. 14.
    Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol. 2002;97:2000–2004.PubMedCrossRefGoogle Scholar
  15. 15.
    Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337:1029–1035.PubMedCrossRefGoogle Scholar
  16. 16.
    Söderholm 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
  17. 17.
    Söderholm JD, Streutker C, Yang P-C, et al. Increased epithelial uptake of protein antigens in the ileum of Crohn’s disease mediated by tumour necrosis factor α. Gut. 2004;53:1817–1824.PubMedCrossRefGoogle Scholar
  18. 18.
    Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR. Interferon-γ and tumor necrosis factor-α synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin chain kinase expression. Am J Pathol. 2005;166:409–419.PubMedCrossRefGoogle Scholar
  19. 19.
    Marini M, Bamias G, Rivera-Nieves J, et al. TNF-α neutralization ameliorates the severity of murine Crohn’s-like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc Natl Acad Sci USA. 2003;100:8366–8371.PubMedCrossRefGoogle Scholar
  20. 20.
    Okamoto R, Watanabe M. Cellular and molecular mechanisms of the epithelial repair in IBD. Dig Dis Sci. 2005;50:S34–S38.PubMedCrossRefGoogle Scholar
  21. 21.
    Blois A, Srebro B, Mandalà M, Corti A, Helle KB, Serck-Hanssen G. The chromogranin A peptide vasostatin-I inhibits gap formation and signal transduction mediated by inflammatory agents in cultured bovine pulmonary and coronary arterial endothelial cells. Regul Pept. 2006;135:78–84.PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrero E, Scabini S, Magni E, et al. Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage. FASEB J. 2004;18:554–556.PubMedGoogle Scholar
  23. 23.
    Helle KB, Corti A, Metz-Boutigue M-H, Tota B. The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. Cell Mol Life Sci. 2007;64:2863–2886.PubMedCrossRefGoogle Scholar
  24. 24.
    Corti A. Chromogranin A and the tumor microenvironment. Cell Mol Neurobiol. 2010;30:1163–1170.PubMedCrossRefGoogle Scholar
  25. 25.
    Corti A, Sanchez LP, Gasparri A, et al. Production and structure characterization of recombinant chromogranin A N-terminal fragments (vasostatins): evidence of dimer-monomer equilibria. Eur J Biochem. 1997;248:692–699.PubMedCrossRefGoogle Scholar
  26. 26.
    Bruewer M, Luegering A, Kucharzik T, et al. Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol. 2003;171:6164–6172.PubMedGoogle Scholar
  27. 27.
    Sanders SE, Madara JL, McGuirk DK, Gelman DS, Colgan SP. Assessment of inflammatory events in epithelial permeability: a rapid screening method using fluorescein dextrans. Epithelial Cell Biol. 1995;4:25–34.PubMedGoogle Scholar
  28. 28.
    Puthenedam M, Wu F, Shetye A, Michaels A, Rhee KJ, Kwon JH. Matrilysin-1 (MMP7) cleaves galectin-3 and inhibits wound healing in intestinal epithelial cells. Inflamm Bowel Dis. 2011;17:260–267.PubMedCrossRefGoogle Scholar
  29. 29.
    Paclik D, Lohse K, Wiedenmann B, Dignass AU, Sturm A. Galectin-2 and -4, but not galectin-1, promote intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism. Inflamm Bowel Dis. 2008;14:1366–1372.PubMedCrossRefGoogle Scholar
  30. 30.
    Ceconi C, Ferrari R, Bachetti T, et al. Chromogranin A in heart failure. A novel neurohumoral factor and a predictor for mortality. Eur Heart J. 2002;23:967–974.PubMedCrossRefGoogle Scholar
  31. 31.
    Pieroni M, Corti A, Tota B, et al. Myocardial production of chromogranin A in human heart: a new regulatory peptide with cardiac function. Eur Heart J. 2007;28:1117–1127.PubMedCrossRefGoogle Scholar
  32. 32.
    Ratti S, Curnis F, Longhi R, et al. Structure-activity relationships of chromogranin A in cell adhesion. J Biol Chem. 2000;275:29257–29263.PubMedCrossRefGoogle Scholar
  33. 33.
    Corti A, Longhi R, Gasparri A, Chen F, Pelagi M, Siccardi AG. Antigenic regions of human chromogranin A and their topographic relationships with structural/functional domains. Eur J Biochem. 1996;235:275–280.PubMedCrossRefGoogle Scholar
  34. 34.
    Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–546.PubMedCrossRefGoogle Scholar
  35. 35.
    MacDermott RP, Sanderson IR, Reinecker HC. The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 1998;4:54–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Sakata A, Yasuda K, Ochiai T, et al. Inhibition of lipopolysaccharide-induced release of interleukin-8 from intestinal epithelial cells by SMA, a novel inhibitor of sphingomyelinase and its therapeutic effect on dextran sulphate sodium-induced colitis in mice. Cell Immunol. 2007;245:24–31.PubMedCrossRefGoogle Scholar
  37. 37.
    van Deventer SJ. Review article Chemokine production by intestinal epithelial cells: a therapeutic target in inflammatory bowel disease? Aliment Pharmacol Ther. 1997;11:S116–S120.CrossRefGoogle Scholar
  38. 38.
    Poritz LS, Garver KI, Green C, Fitzpatrick L, Ruggiero F, Koltun WA. Loss of the tight junction protein ZO.1 in dextran sulfate sodium induced colitis. J Surg Res. 2007;140:12–19.PubMedCrossRefGoogle Scholar
  39. 39.
    Vetrano S, Rescigno M, Cera MR, et al. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology. 2008;135:173–184.PubMedCrossRefGoogle Scholar
  40. 40.
    Colombo B, Longhi R, Marinzi C, et al. Cleavage of chromogranin A N-terminal domain by plasmin provides a new mechanism for regulating cell adhesion. J Biol Chem. 2002;277:45911–45919.PubMedCrossRefGoogle Scholar
  41. 41.
    Guimbaud R, Bertrand V, Chauvelot-Moachon L, et al. Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis. Am J Gastroenterol. 1998;93:2397–2404.PubMedCrossRefGoogle Scholar
  42. 42.
    Arijs I, De Hertogh G, Machiels K, et al. Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. Am J Gastroenterol. 2011;106:748–761.PubMedCrossRefGoogle Scholar
  43. 43.
    Aldhous MC, Noble CL, Satsangi J. Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One. 2009;4:e6285.PubMedCrossRefGoogle Scholar
  44. 44.
    Gitter AH, Wullstein F, Fromm M, Schulzke JD. Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging. Gastroenterol. 2001;121:1320–1328.CrossRefGoogle Scholar
  45. 45.
    Gasparri A, Sidoli A, Sanchez LP, et al. Chromogranin A fragments modulate cell adhesion. Identification and characterization of a pro-adhesive domain. J Biol Chem. 1997;272:20835–20843.PubMedCrossRefGoogle Scholar
  46. 46.
    Colombo F, Curnis C, Foglieni A, et al. Chromogranin A expression in neoplastic cells affects tumor growth and morphogenesis in mouse models. Cancer Res. 2002;62:941–946.PubMedGoogle Scholar
  47. 47.
    Zhang XY, De Meester I, Lambeir AM, et al. Study of the enzymatic degradation of vasostatin I and II and their precursor chromogranin A by dipeptidyl peptidase IV using high-performance liquid chromatography/electrospray mass spectrometry. J Mass Spectrom. 1999;34:255–263.PubMedCrossRefGoogle Scholar
  48. 48.
    Clemente MG, De Virgiliis S, Kang JS, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52:218–223.PubMedCrossRefGoogle Scholar
  49. 49.
    Drago S, El Asmar R, Di Pierro M, et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41:408–419.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Cristiano Rumio
    • 1
  • Giuseppina F. Dusio
    • 1
  • Barbara Colombo
    • 2
  • Anna Gasparri
    • 2
  • Diego Cardani
    • 1
  • Fabrizio Marcucci
    • 3
    • 4
    Email author
  • Angelo Corti
    • 2
  1. 1.iMIL—Italian Mucosal Immunity Laboratory, Dipartimento di Morfologia Umana e Scienze Biomediche “Città Studi”Università degli Studi di MilanoMilanoItaly
  2. 2.Division of Molecular OncologySan Raffaele Scientific InstituteMilanItaly
  3. 3.Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute (CNESPS), Istituto Superiore di Sanità (ISS)RomaItaly
  4. 4.Hepatology Association of CalabriaPellaro Reggio CalabriaItaly

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