The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis

Paolo Biancheri; Sylvia LF Pender; Francesca Ammoscato; Paolo Giuffrida; Gianluca Sampietro; Sandro Ardizzone; Amir Ghanbari; Renata Curciarello; Alessandra Pasini; Giovanni Monteleone; Gino R Corazza; Thomas T MacDonald; Antonio Di Sabatino

doi:10.1186/1755-1536-6-13

journal article Jul 08, 2013

The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis

Paolo Biancheri Sylvia LF Pender Francesca Ammoscato Paolo Giuffrida

Gianluca Sampietro

Sandro Ardizzone Amir Ghanbari Renata Curciarello Alessandra Pasini Giovanni Monteleone

Gino R Corazza Thomas T MacDonald Antonio Di Sabatino

Fibrogenesis & Tissue Repair Vol. 6 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1186/1755-1536-6-13

Abstract

AbstractBackgroundInterleukin (IL)-17A and IL-17E (also known as IL-25) have been implicated in fibrosis in various tissues. However, the role of these cytokines in the development of intestinal strictures in Crohn’s disease (CD) has not been explored. We investigated the levels of IL-17A and IL-17E and their receptors in CD strictured and non-strictured gut, and the effects of IL-17A and IL-17E on CD myofibroblasts.ResultsIL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas. Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production. IL-17A, but not IL-17E, significantly inhibited myofibroblast migration, and also significantly upregulated matrix metalloproteinase (MMP)-3, MMP-12, tissue inhibitor of metalloproteinase-1 and collagen production by myofibroblasts from strictured CD tissues.ConclusionsOur results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD. Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD.

Topics

No keywords indexed for this article. Browse by subject →

References

38

[1]

Mechanisms of fibrosis: therapeutic translation for fibrotic disease

Thomas A Wynn, Thirumalai R Ramalingam

Nature Medicine 2012 10.1038/nm.2807

[2]

Gabbiani G: The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003, 200: 500-503. 10.1002/path.1427. 10.1002/path.1427

[3]

Wynn TA: Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004, 4: 583-594. 10.1038/nri1412. 10.1038/nri1412

[4]

Gaffen SL: Recent advances in the IL-17 cytokine family. Curr Opin Immunol. 2011, 23: 613-619. 10.1016/j.coi.2011.07.006. 10.1016/j.coi.2011.07.006

[5]

Valente AJ, Yoshida T, Gardner JD, Somanna N, Delafontaine P, Chandrasekar B: Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1. Cell Signal. 2012, 24: 560-568. 10.1016/j.cellsig.2011.10.010. 10.1016/j.cellsig.2011.10.010

[6]

Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Osterreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T: Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012, 143: 765-776. 10.1053/j.gastro.2012.05.049. 10.1053/j.gastro.2012.05.049

[7]

Okamoto Y, Hasegawa M, Matsushita T, Hamaguchi Y, Huu DL, Iwakura Y, Fujimoto M, Takehara K: Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 2012, 64: 3726-3735. 10.1002/art.34643. 10.1002/art.34643

[8]

Mi S, Li Z, Yang HZ, Liu H, Wang JP, Ma YG, Wang XX, Liu HZ, Sun W, Hu ZW: Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol. 2011, 187: 3003-3014. 10.4049/jimmunol.1004081. 10.4049/jimmunol.1004081

[9]

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts

Séverine Létuvé, Stéphane Lajoie-Kadoch, Séverine Audusseau et al.

Journal of Allergy and Clinical Immunology 2006 10.1016/j.jaci.2005.10.025

[10]

IL-25 drives remodelling in allergic airways disease induced by house dust mite

Lisa G Gregory, Carla P Jones, Simone A Walker et al.

Thorax 2013 10.1136/thoraxjnl-2012-202003

[11]

Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles CH, Rampton DS, Corazza GR, Monteleone G, Di Sabatino A, Macdonald TT: Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut. 2009, 58: 1629-1636. 10.1136/gut.2009.182170. 10.1136/gut.2009.182170

[12]

Caruso R, Sarra M, Stolfi C, Rizzo A, Fina D, Fantini MC, Pallone F, MacDonald TT, Monteleone G: Interleukin-25 inhibits interleukin-12 production and Th1 cell-driven inflammation in the gut. Gastroenterology. 2009, 136: 2270-2279. 10.1053/j.gastro.2009.02.049. 10.1053/j.gastro.2009.02.049

[13]

Burke JP, Mulsow JJ, O’Keane C, Docherty NG, Watson RW, O’Connell PR: Fibrogenesis in Crohn’s disease. Am J Gastroenterol. 2007, 102: 439-448. 10.1111/j.1572-0241.2006.01010.x. 10.1111/j.1572-0241.2006.01010.x

[14]

Regan MC, Flavin BM, Fitzpatrick JM, O’Connell PR: Stricture formation in Crohn’s disease: the role of intestinal fibroblasts. Ann Surg. 2000, 231: 46-50. 10.1097/00000658-200001000-00007. 10.1097/00000658-200001000-00007

[15]

Andoh A, Bamba S, Brittan M, Fujiyama Y, Wright NA: Role of intestinal subepithelial myofibroblasts in inflammation and regenerative response in the gut. Pharmacol Ther. 2007, 114: 94-106. 10.1016/j.pharmthera.2006.12.004. 10.1016/j.pharmthera.2006.12.004

[16]

Di Sabatino A, Jackson CL, Pickard KM, Buckley M, Rovedatti L, Leakey NA, Picariello L, Cazzola P, Monteleone G, Tonelli F, Corazza GR, MacDonald TT, Pender SL: Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn’s disease strictures. Gut. 2009, 58: 777-789. 10.1136/gut.2008.149096. 10.1136/gut.2008.149096

[17]

Okuno T, Andoh A, Bamba S, Araki Y, Fujiyama Y, Fujiyama M, Bamba T: Interleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand J Gastroenterol. 2002, 37: 317-324. 10.1080/003655202317284228. 10.1080/003655202317284228

[18]

Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT: Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005, 6: 1123-1132. 10.1038/ni1254. 10.1038/ni1254

[19]

Phenotypic and functional features of human Th17 cells

Francesco Annunziato, Lorenzo Cosmi, Veronica Santarlasci et al.

The Journal of Experimental Medicine 2007 10.1084/jem.20070663

[20]

Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007, 13: 139-145. 10.1038/nm1551. 10.1038/nm1551

[21]

Monteleone I, Sarra M, Del Vecchio BG, Paoluzi OA, Franzè E, Fina D, Fabrizi A, MacDonald TT, Pallone F, Monteleone G: Characterization of IL-17A-producing cells in celiac disease mucosa. J Immunol. 2010, 184: 2211-2218. 10.4049/jimmunol.0901919. 10.4049/jimmunol.0901919

[22]

IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease

T Kobayashi, S Okamoto, T Hisamatsu et al.

Gut 2008 10.1136/gut.2007.135053

[23]

Sarra M, Pallone F, MacDonald TT, Monteleone G: IL-23/IL-17 axis in IBD. Inflamm Bowel Dis. 2010, 16: 1808-1813. 10.1002/ibd.21248. 10.1002/ibd.21248

[24]

Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA: Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010, 207: 535-552. 10.1084/jem.20092121. 10.1084/jem.20092121

[25]

Guan Q, Ma Y, Hillman CL, Qing G, Ma AG, Weiss CR, Zhou G, Bai A, Warrington RJ, Bernstein CN, Peng Z: 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. 10.2119/molmed.2010.00252

[26]

Zorzi F, Monteleone I, Sarra M, Calabrese E, Marafini I, Cretella M, Sedda S, Biancone L, Pallone F, Monteleone G: Distinct profiles of effector cytokines mark the different phases of Crohn’s disease. PLoS One. 2013, 8: e54562-10.1371/journal.pone.0054562. 10.1371/journal.pone.0054562

[27]

Bamba S, Andoh A, Yasui H, Araki Y, Bamba T, Fujiyama Y: Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17. J Gastroenterol. 2003, 38: 548-554. 10.1007/s00535-002-1101-8

[28]

Lawrance IC, Wu F, Leite AZ, Willis J, West GA, Fiocchi C, Chakravarti S: A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B. Gastroenterology. 2003, 125: 1750-1761. 10.1053/j.gastro.2003.08.027. 10.1053/j.gastro.2003.08.027

[29]

Gunther U, Schuppan D, Bauer M, Matthes H, Stallmach A, Schmitt-Gräff A, Riecken EO, Herbst H: Fibrogenesis and fibrolysis in collagenous colitis. Patterns of procollagen types I and IV, matrix-metalloproteinase-1 and −13, and TIMP-1 gene expression. Am J Pathol. 1999, 155: 493-503. 10.1016/S0002-9440(10)65145-0. 10.1016/s0002-9440(10)65145-0

[30]

Sharkhuu T, Matthaei KI, Forbes E, Mahalingam S, Hogan SP, Hansbro PM, Foster PS: Mechanism of interleukin-25 (IL-17E)-induced pulmonary inflammation and airways hyper-reactivity. Clin Exp Allergy. 2006, 36: 1575-1583. 10.1111/j.1365-2222.2006.02595.x. 10.1111/j.1365-2222.2006.02595.x

[31]

Monteleone G, Pallone F, Macdonald TT: Interleukin-25: a two-edged sword in the control of immune-inflammatory responses. Cytokine Growth Factor Rev. 2010, 21: 471-475. 10.1016/j.cytogfr.2010.05.001. 10.1016/j.cytogfr.2010.05.001

[32]

Fichtner-Feigl S, Strober W, Geissler EK, Schlitt HJ: Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis. Mucosal Immunol. 2008, 1 (Suppl.1): S24-S27. 10.1038/mi.2008.41

[33]

Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SP: Secukinumab in Crohn’s Disease Study Group: Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012, 61: 1693-1700. 10.1136/gutjnl-2011-301668. 10.1136/gutjnl-2011-301668

[34]

Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s disease activity index: National Cooperative Crohn’s disease study. Gastroenterology. 1976, 70: 439-444. 10.1016/s0016-5085(76)80163-1

[35]

Maglinte DD, Kelvin FM, Sandrasegaran K, Nakeeb A, Romano S, Lappas JC, Howard TJ: Radiology of small bowel obstruction: contemporary approach and controversies. Abdom Imaging. 2005, 30: 160-178. 10.1007/s00261-004-0211-6. 10.1007/s00261-004-0211-6

[36]

Di Sabatino A, Pender SLF, Jackson CL, Prothero JD, Gordon JN, Picariello L, Rovedatti L, Docena G, Monteleone G, Rampton DS, Tonelli F, Corazza GR, MacDonald TT: Functional modulation of Crohn’s disease myofibroblasts by anti-TNF antibodies. Gastroenterology. 2007, 133: 137-149. 10.1053/j.gastro.2007.04.069. 10.1053/j.gastro.2007.04.069

[37]

Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT: A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol. 1997, 158: 1582-1590. 10.4049/jimmunol.158.4.1582

[38]

Rodriguez LG, Wu X, Guan JL: Wound-healing assay. Methods Mol Biol. 2005, 294: 23-29.

Cited By

94

Interleukin 17A in the fibrotic-related processes in endometrosis in the mare

Agnieszka Sadowska, Anna Wójtowicz · 2026

Theriogenology

An intricate relationship between fibrosis and autoimmune diseases: a specific focus on unraveling its molecular, immunological, and epigenetic drivers

Manoviraj Gajendra Morey, Gouri H. Illanad · 2026

Frontiers in Immunology

Cellular and Molecular Mechanisms of Intestinal Fibrosis

Xiaomin Wu, Xiaoxuan Lin · 2023

Gut and Liver

The Molecular Mechanisms of Intestinal Inflammation and Fibrosis in Crohn’s Disease

Yuki Hayashi, Hiroshi Nakase · 2022

Frontiers in Physiology

Mechanism of fibrosis and stricture formation in Crohn's disease

Johannes Alfredsson, Mary Jo Wick · 2020

Scandinavian Journal of Immunology

The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review

Sun-Mi Yun, Seok-Ho Kim · 2019

Frontiers in Pharmacology

The Role of Cytokines in the Fibrotic Responses in Crohn’s Disease

Renata Curciarello, Guillermo H. Docena · 2017

Frontiers in Medicine

Metrics

94

Citations

38

References

Details

Published: Jul 08, 2013
Vol/Issue: 6(1)

Authors

Luigi Sacco Department of Clinical and Biomedical Sciences, University of Milano, Milano, Italy; Division of Gastroenterology, ASST Fatebenefratelli - Sacco, Milano, Italy

Cite This Article

Paolo Biancheri, Sylvia LF Pender, Francesca Ammoscato, et al. (2013). The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis & Tissue Repair, 6(1). https://doi.org/10.1186/1755-1536-6-13

The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis

You May Also Like