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Role of Interleukin-17 in Pathogenesis of Intestinal Fibrosis in Mice

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Abstract

Background

The level of interleukin (IL)-17 is commonly increased in serum and intestinal mucosa of patients with inflammatory bowel disease, especially Crohn’s disease with intestinal stricture. However, the role of IL-17 in the pathogenesis of intestinal fibrosis and the effect of anti-IL-17 treatment on intestinal fibrosis remain unclear; these issues are studied in vivo in this study.

Method

A total of 24 wild female Balb/c mice (18–22 g) were randomly divided into three groups: (1) control group, (2) 2,4,6-trinitrobenzenesulfonic acid (TNBS) + immunoglobulin G (IgG) group, and (3) TNBS + anti-IL-17 group. The levels of IL-17, IL-1β, transforming growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α in blood and of collagen 3 and IL-17 in gut were measured by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) levels of collagen 3, IL-17, TNF-α, tissue inhibitor of metalloproteinase (TIMP)-1, and matrix metalloproteinase (MMP)-2 in gut were measured by reverse-transcription polymerase chain reaction. The protein expression of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 were measured by immunoblot analysis. Collagen deposition was evaluated by standard hematoxylin and eosin and Masson’s trichrome staining.

Results

The profibrogenic cytokines IL-17, IL-1β, TGF-β1, and TNF-α in serum, mRNA levels of collagen 3, IL-17, TNF-α, TIMP-1, and MMP-2, and protein levels of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 in gut were upregulated in TNBS-induced intestinal fibrosis mice. Treatment with anti-IL-17 antibody significantly alleviated intestinal fibrosis and reduced both mRNA and protein levels of collagen 3, TNF-α, TIMP-1, and MMP-2. The levels of profibrogenic cytokines IL-1β, TGF-β1, and TNF-α were also decreased in mice treated with anti-IL-17 antibody.

Conclusions

IL-17 contributes to the pathogenesis of intestinal fibrosis, and anti-IL-17 therapy may weaken this effect by downregulating expression of profibrogenic cytokines and disturbing the MMP/TIMPs balance.

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References

  1. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Burke JP, Mulsow JJ, O’Keane C, et al. Fibrogenesis in Crohn’s disease. Am J Gastroenterol. 2007;102:439–448.

    Article  CAS  PubMed  Google Scholar 

  3. Van Assche G, Geboes K, Rutgeerts P. Medical therapy for Crohn’s disease strictures. Inflamm Bowel Dis. 2004;10:55–60.

    Article  PubMed  Google Scholar 

  4. Latella G, Sferra R, Speca S, et al. Can we prevent, reduce or reverse intestinal fibrosis in IBD? Eur Rev Med Pharmacol Sci. 2013;17:1283–1304.

    CAS  PubMed  Google Scholar 

  5. Yagi Y, Andoh A, Inatomi O, et al. Inflammatory responses induced by interleukin-17 family members in human colonic subepithelial myofibroblasts. J Gastroenterol. 2007;42:746–753.

    Article  CAS  PubMed  Google Scholar 

  6. Honzawa Y, Nakase H, Shiokawa M, et al. Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn’s disease. Gut. 2014;63:1902–1912.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang HJ, Zhang YN, Zhou H, et al. IL-17A promotes initiation and development of intestinal fibrosis through EMT. Dig Dis Sci. 2018;63:2898–2909.

    Article  CAS  PubMed  Google Scholar 

  8. Biancheri P, Pender SL, Ammoscato F, et al. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013;6:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kihara N, de la Fuente SG, Fujino K, et al. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut. 2003;52:713–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Latella G, Rogler G, Bamias G, et al. Results of the 4th scientific workshop of the ECCO (I): pathophysiology of intestinal fibrosis in IBD. J Crohns Colitis. 2014;8:1147–1165.

    Article  PubMed  Google Scholar 

  11. Speca S, Giusti I, Rieder F, et al. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol. 2012;18:3635–3661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sands BE, Kaplan GG. The role of TNFα in ulcerative colitis. J Clin Pharmacol. 2007;47:930–941.

    Article  CAS  PubMed  Google Scholar 

  13. Chen Y, Ge W, Xu L, et al. miR-200b is involved in intestinal fibrosis of Crohn’s disease. Int J Mol Med. 2012;29:601–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lawrance IC, Wu F, Leite AZ, et al. A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B. Gastroenterology. 2003;125:1750–1761.

    Article  CAS  PubMed  Google Scholar 

  15. Breynaert C, de Bruyn M, Arijs I, et al. Genetic deletion of tissue inhibitor of metalloproteinase-1/TIMP-1 alters inflammation and attenuates fibrosis in dextran sodium sulphate-induced murine models of colitis. J Crohns Colitis. 2016;10:1336–1350.

    Article  PubMed  Google Scholar 

  16. Li H, Song J, Niu G, et al. TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. Pathol Res Pract. 2018;214:217–227.

    Article  CAS  PubMed  Google Scholar 

  17. Harrington LE, Hatton RD, Mangan PR, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–1861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57:1682–1689.

    Article  CAS  PubMed  Google Scholar 

  20. Sarra M, Pallone F, Macdonald TT, et al. IL-23/IL-17 axis in IBD. Inflamm Bowel Dis. 2010;16:1808–1813.

    Article  PubMed  Google Scholar 

  21. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–350.

    Article  CAS  PubMed  Google Scholar 

  22. Wilson MS, Madala SK, Ramalingam TR, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207:535–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gasse P, Riteau N, Vacher R, et al. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PLoS ONE. 2011;6:e23185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Okamoto Y, Hasegawa M, Matsushita T, et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 2012;64:3726–3735.

    Article  CAS  PubMed  Google Scholar 

  25. Valente AJ, Yoshida T, Gardner JD, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Meng F, Wang K, Aoyama T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012;143:765–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zorzi F, Monteleone I, Sarra M, et al. Distinct profiles of effector cytokines mark the different phases of Crohn’s disease. PLoS ONE. 2013;8:e54562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guan Q, Ma Y, Hillman CL, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang Y, Huang D, Gao W, et al. Lack of IL-17 signaling decreases liver fibrosis in murine schistosomiasis japonica. Int Immunol. 2015;27:317–325.

    Article  CAS  PubMed  Google Scholar 

  30. Cipolla E, Fisher AJ, Gu H, et al. IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis. FASEB J. 2017;31:5543–5556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gutcher I, Donkor MK, Ma Q, et al. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34:396–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee YK, Turner H, Maynard CL, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang S, Huang D, Weng J, et al. Neutralization of interleukin-17 attenuates cholestatic liver fibrosis in mice. Scand J Immunol. 2016;83:102–108.

    Article  CAS  PubMed  Google Scholar 

  34. Mi S, Li Z, Yang HZ, 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.

    Article  CAS  PubMed  Google Scholar 

  35. Medina C, Santos-Martinez MJ, Santana A, et al. Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis. J Pathol. 2011;224:461–472.

    Article  CAS  PubMed  Google Scholar 

  36. Shih DQ, Zheng L, Zhang X, et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 2014;7:1492–1503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wengrower D, Zanninelli G, Latella G, et al. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats. Can J Gastroenterol. 2012;26:33–39.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hueber W, Sands BE, Lewitzky S, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Targan SR, Feagan B, Vermeire S, et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am J Gastroenterol. 2016;111:1599–1607.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang Z, Zheng M, Bindas J, et al. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006;12:382–388.

    Article  PubMed  Google Scholar 

  41. O’Connor W Jr, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009;10:603–609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

This article was supported by the Health Commission of Hubei Province Foundation (No. WJ2019M205).

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Authors and Affiliations

  1. Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Donghu Road 169, Wuhan, 430071, People’s Republic of China

    Jian Li, Lan Liu, Qiu Zhao & Min Chen

  2. The Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, People’s Republic of China

    Jian Li, Lan Liu, Qiu Zhao & Min Chen

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  1. Jian Li
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  2. Lan Liu
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Correspondence to Min Chen.

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Li, J., Liu, L., Zhao, Q. et al. Role of Interleukin-17 in Pathogenesis of Intestinal Fibrosis in Mice. Dig Dis Sci 65, 1971–1979 (2020). https://doi.org/10.1007/s10620-019-05969-w

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