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IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT

  • Hui-Jing Zhang
  • Yi-Ning Zhang
  • Huan Zhou
  • Lin Guan
  • Yue Li
  • Ming-Jun Sun
Original Article

Abstract

Background

Intestinal fibrosis is a common complication of Crohn’s disease (CD). Its exact mechanism is still unclear, and effective treatments to control or reverse the fibrosis process are unavailable. Epithelial–mesenchymal transition (EMT) may promote intestinal fibrosis by increasing deposition of extracellular matrix protein. IL-17A is a pro-inflammatory cytokine, and it has been shown as a profibrotic factor as its association with fibrosis of multiple organs was reported.

Aims

To assess the roles of IL-17A and EMT in the initiation and development of intestinal fibrosis and to verify the potential inductive effect of IL-17A on EMT.

Methods

In this study, we evaluated the expression of IL-17A and EMT-related genes in colonic mucosal biopsy tissues of CD patients and control individuals. Then, we examined the changes of EMT-related genes and fibrosis-related genes of IEC-6 cells which cultured for 72 h under increasing concentrations of IL-17A or with TGF-β1, to verify the potential inductive effect of IL-17A on EMT in vitro. We blocked the IL-17A of the mouse model of TNBS-induced experimental intestinal colitis and fibrosis to further verify the potential inductive effect of IL-17A on EMT in vivo.

Results

We found the occurrence of EMT and high-level expression of IL-17A in intestinal mucosa of CD patients. Using IEC-6 cells, we showed that IL-17A may induce EMT in intestinal epithelial cells that come with reduced E-cadherin expression and increased expression of vimentin, snail, and α-SMA. We further found that anti-IL-17A treatment alleviated intestinal fibrosis through reducing EMT in mouse intestine.

Conclusions

Our study confirmed the involvement of IL-17A in the development of intestinal fibrosis through inducing EMT.

Keywords

Colitis fibrosis IL-17A EMT TNBS 

Notes

Acknowledgments

This work was supported by Liaoning Province Science and Technology Project (2013225049). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author’s contribution

MJ-S was involved in conception and design, interpretation of data, and manuscript revision. HJ-Z, YN-Z, and HZ performed the experiments. LG and YL collected the biopsy samples. HJ-Z YN-Z analyzed the data. MJ-S contributed reagents/materials/analysis tools. HJ-Z and YN-Z wrote the paper. All authors approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

All authors do not have a commercial or other association that might pose a conflict of interest.

Supplementary material

10620_2018_5234_MOESM1_ESM.doc (59 kb)
Supplementary material 1 (DOC 59 kb)

References

  1. 1.
    Latella G, Di Gregorio J, Flati V, Rieder F, Lawrance IC. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand J Gastroenterol. 2015;50:53–65.CrossRefPubMedGoogle Scholar
  2. 2.
    Jeuring S, Van den Heuvel T, Zeegers M, et al. Disease behavior in Crohn’s disease patients diagnosed in the biological era—a Dutch population-based IBD-SL cohort study. Gastroenterology. 2015;148:2.CrossRefGoogle Scholar
  3. 3.
    Cosnes J, Bourrier A, Nion-Larmurier I, Sokol H, Beaugerie L, et al. Factors affecting outcomes in Crohn’s disease over 15 years. Gut. 2012;61:1140–1145.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pittet V, Rogler G, Michetti P, Fournier N, Vader JP, et al. Penetrating or stricturing diseases are the major determinants of time to first and repeat resection surgery in Crohn’s disease. Digestion. 2013;87:212–221.CrossRefPubMedGoogle Scholar
  5. 5.
    Latella G, Papi C. Crucial steps in the natural history of inflammatory bowel disease. World J Gastroenterol. 2012;18:3790–3799.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bernstein CN, Loftus EV Jr, Ng SC, Lakatos PL, Moum B, et al. Hospitalisations and surgery in Crohn’s disease. Gut. 2012;61:622–629.CrossRefPubMedGoogle Scholar
  7. 7.
    Latella G, Sferra R, Vetuschi A, Zanninelli G, D’Angelo A, et al. Prevention of colonic fibrosis by Boswellia and Scutellaria extracts in rats with colitis induced by 2,4,5-trinitrobenzene sulphonic acid. Eur J Clin Invest. 2008;38:410–420.CrossRefPubMedGoogle Scholar
  8. 8.
    Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol. 2012;18:3635–3661.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rieder F, Fiocchi C. Intestinal fibrosis in inflammatory bowel disease—current knowledge and future perspectives. J Crohns Colitis. 2008;2:279–290.CrossRefPubMedGoogle Scholar
  10. 10.
    Rieder F, Fiocchi C, Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:e346.CrossRefGoogle Scholar
  11. 11.
    Lawrance IC, Rogler G, Bamias G, Breynaert C, Florholmen J, et al. Cellular and molecular mediators of intestinal fibrosis. J Crohns Colitis. 2017;11:1491–1503.CrossRefPubMedGoogle Scholar
  12. 12.
    Rieder F. The gut microbiome in intestinal fibrosis: Environmental protector or provocateur? Sci Transl Med. 2013;5:190ps110.CrossRefGoogle Scholar
  13. 13.
    Scharl M, Huber N, Lang S, Furst A, Jehle E, et al. Hallmarks of epithelial to mesenchymal transition are detectable in Crohn’s disease associated intestinal fibrosis. Clin Transl Med. 2015;4:1.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Scharl M, Frei S, Pesch T, Kellermeier S, Arikkat J, et al. Interleukin-13 and transforming growth factor beta synergise in the pathogenesis of human intestinal fistulae. Gut. 2013;62:63–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, et al. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem. 2010;285:20202–20212.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rieder F, Kessler SP, West GA, Bhilocha S, de la Motte C, et al. Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am J Pathol. 2011;179:2660–2673.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. Wound healing and fibrosis in intestinal disease. Gut. 2007;56:130–139.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Uehara H, Nakagawa T, Katsuno T, Sato T, Isono A, et al. Emergence of fibrocytes showing morphological changes in the inflamed colonic mucosa. Dig Dis Sci. 2010;55:253–260.  https://doi.org/10.1007/s10620-009-0730-7.CrossRefPubMedGoogle Scholar
  19. 19.
    Brittan M, Chance V, Elia G, Poulsom R, Alison MR, et al. A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology. 2005;128:1984–1995.CrossRefPubMedGoogle Scholar
  20. 20.
    Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt. Cell. 2016;166:21–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor budding: the name is EMT. Partial EMT. J Clin Med. 2016;5:51.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–196.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yang J, Zhou CZ, Zhu R, Fan H, Liu XX, et al. miR-200b-containing microvesicles attenuate experimental colitis associated intestinal fibrosis by inhibiting epithelial-mesenchymal transition. J Gastroenterol Hepatol. 2017;32:1966–1974.CrossRefPubMedGoogle Scholar
  24. 24.
    Scharl M, Bruckner RS, Rogler G. The two sides of the coin: similarities and differences in the pathomechanisms of fistulas and stricture formations in irritable bowel disease. United Eur Gastroenterol J. 2016;4:506–514.CrossRefGoogle Scholar
  25. 25.
    Okamoto Y, Hasegawa M, Matsushita T, Hamaguchi Y, Huu DL, et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 2012;64:3726–3735.CrossRefPubMedGoogle Scholar
  26. 26.
    Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207:535–552.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tan Z, Qian X, Jiang R, Liu Q, Wang Y, et al. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol. 2013;191:1835–1844.CrossRefPubMedGoogle Scholar
  28. 28.
    Guan Q, Ma Y, Hillman CL, Qing G, Ma AG, et al. Targeting IL-12/IL-23 by employing a p40 peptide-based vaccine ameliorates TNBS-induced acute and chronic murine colitis. Mol Med. 2011;17:646–656.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Latella G, Caprilli R, Travis S. In favour of early surgery in Crohn’s disease: a hypothesis to be tested. J Crohns Colitis. 2011;5:1–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Quencer KB, Nimkin K, Mino-Kenudson M, Gee MS. Detecting active inflammation and fibrosis in pediatric Crohn’s disease: prospective evaluation of MR-E and CT-E. Abdominal Imaging. 2013;38:705–713.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Scheiffele F, Fuss IJ. Induction of TNBS colitis in mice. Curr Protoc Immunol. 2002;49:19.Google Scholar
  32. 32.
    Fichtner-Feigl S, Fuss IJ, Young CA, Watanabe T, Geissler EK, et al. Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis. J Immunol. 2007;178:5859–5870.CrossRefPubMedGoogle Scholar
  33. 33.
    Alex P, Zachos NC, Nguyen T, Gonzales L, Chen TE, et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis. 2009;15:341–352.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dieleman LA, Pena AS, Meuwissen SG, van Rees EP. Role of animal models for the pathogenesis and treatment of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1997;223:99–104.PubMedGoogle Scholar
  35. 35.
    Videla S, Vilaseca J, Medina C, Mourelle M, Guarner F, et al. Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis. J Pharmacol Exp Ther. 2006;316:940–945.CrossRefPubMedGoogle Scholar
  36. 36.
    Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–546.CrossRefPubMedGoogle Scholar
  37. 37.
    Lawrance IC, Wu F, Leite AZ, Willis J, West GA, et al. A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B. Gastroenterology. 2003;125:1750–1761.CrossRefPubMedGoogle Scholar
  38. 38.
    Bettenworth D, Rieder F. Reversibility of stricturing Crohn’s disease-fact or fiction? Inflamm Bowel Dis. 2016;22:241–247.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fiocchi C, Lund PK. Themes in fibrosis and gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2011;300:G677–G683.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rieder F, Fiocchi C. Mechanisms of tissue remodeling in inflammatory bowel disease. Dig Dis. 2013;31:186–193.  https://doi.org/10.1159/000353364.CrossRefPubMedGoogle Scholar
  41. 41.
    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–428.CrossRefPubMedGoogle Scholar
  42. 42.
    Biancheri P, Pender SL, Ammoscato F, Giuffrida P, Sampietro G, et al. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013;6:13.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mi S, Li Z, Yang HZ, Liu H, Wang JP, et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol. 2011;187:3003–3014.CrossRefPubMedGoogle Scholar
  44. 44.
    Vittal R, Fan L, Greenspan DS, Mickler EA, Gopalakrishnan B, et al. IL-17 induces type V collagen overexpression and EMT via TGF-beta-dependent pathways in obliterative bronchiolitis. Am J Physiol Lung Cell Mol Physiol. 2013;304:L401–L414.CrossRefPubMedGoogle Scholar
  45. 45.
    Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010;24:1838–1851.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mifflin RC, Pinchuk IV, Saada JI, Powell DW. Intestinal myofibroblasts: targets for stem cell therapy. Am J Physiol Gastrointest Liver Physiol. 2011;300:G684–G696.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhu MY, Lu YM, Ou YX, Zhang HZ, Chen WX. Dynamic progress of 2,4,6-trinitrobenzene sulfonic acid induced chronic colitis and fibrosis in rat model. J Dig Dis. 2012;13:421–429.CrossRefPubMedGoogle Scholar
  48. 48.
    Fichtner-Feigl S, Strober W, Geissler EK, Schlitt HJ. Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis. Mucosal Immunol. 2008;1:S24–S27.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment options for inflammatory bowel diseases. J Gastroenterol. 2018;53:585–590.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zorzi F, Monteleone I, Sarra M, Calabrese E, Marafini I, et al. Distinct profiles of effector cytokines mark the different phases of Crohn’s disease. Gastroenterology. 2013;144:S820–S820.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hui-Jing Zhang
    • 1
  • Yi-Ning Zhang
    • 1
  • Huan Zhou
    • 1
  • Lin Guan
    • 1
  • Yue Li
    • 1
  • Ming-Jun Sun
    • 1
  1. 1.Department of EndoscopyThe First Affiliated Hospital of China Medical UniversityShenyangChina

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