Advertisement

Effects and Mechanism of Constitutive TL1A Expression on Intestinal Mucosal Barrier in DSS-Induced Colitis

  • Mingyue Yang
  • Wenxiu Jia
  • Dong Wang
  • Fei Han
  • Weiwei Niu
  • Hong Zhang
  • David Q. Shih
  • Xiaolan ZhangEmail author
Original Article
  • 51 Downloads

Abstract

Objective

The role of TL1A in the intestinal mucosa barrier in inflammatory bowel disease (IBD) is still unclear. This study was aimed to investigate the expression levels of tight junction protein (TJ), myosin light chain kinase (MLCK), MyD88 and tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF6) and how TL1A influences the intestinal barrier in IBD.

Methods

The mouse models of IBD were built using FMS-TL1A-GFP-transgenic mice and wild-type mice. The morphological and histopathological changes, bacterial translocation, permeability of colonic mucosa, and LPS level were assessed. Caco-2 cells were used to further investigate the association between TL1A and TNF-α and LPS. The protein level and mRNA changes of TJ proteins including ZO-1, occluding, JAMA, claudin-1, claudin-2, and claudin-3 were investigated using Western blot and real-time PCR. Protein changes of MLCK, MyD88 and TNF receptor-associated factor-6 (TRAF6), and TNF-α mRNA in the mouse colon were further assessed.

Results

The IBD models were successfully built. Cooper HS score and histopathological score of the colon were higher in DSS/WT group than in control/WT group (P < 0.05), higher in DSS/Tg group than in control/Tg group (P < 0.05), and higher in DSS/Tg group than in DSS/WT group. PAS, colonic permeability of the colon, and FITC-D examination showed the similar results and trends. Compared with control/WT group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/WT group (P < 0.05). Compared with control/Tg group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/Tg group. Compared with Caco-2 + TNF-α group, the expression level of occludin and claudin-1 in Caco-2 + LV-TNFSF15 + TNF-α group was significantly lower (P < 0.05); p-MLC level was significantly higher. Compared with Caco-2 + LPS group, the expression level of occludin and claudin-1 significantly decreased in Caco-2 + LV-TNFSF15 + LPS group; MyD88 and TRAF6 expression level significantly increased.

Conclusion

The results suggested that TL1A could impair intestinal epithelial barrier in the mouse model of IBD and might regulate TJ expression via MLCK/p-MLC pathway and LPS-mediated MyD88/TRAF6 pathway.

Keywords

Inflammatory bowel disease Intestinal mucosal barrier TL1A Tumor necrosis factor-α ASIV 

Notes

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing interests.

References

  1. 1.
    Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627–1640.CrossRefGoogle Scholar
  2. 2.
    Zhai H, Liu A, Huang W, et al. Increasing rate of inflammatory bowel disease: a 12-year retrospective study in NingXia, China. BMC Gastroenterol. 2016;16:1–7.CrossRefGoogle Scholar
  3. 3.
    Ma TY, Iwamoto GK, Hoa NT, et al. TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol. 2004;286:G367.CrossRefGoogle Scholar
  4. 4.
    Fréour T, Jarry A, Bach-Ngohou K, et al. TACE inhibition amplifies TNF-alpha-mediated colonic epithelial barrier disruption. Int J Mol Med. 2009;23:41–48.Google Scholar
  5. 5.
    Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity. 2002;16:479–492.CrossRefGoogle Scholar
  6. 6.
    Cunningham KE, Turner JR. Myosin light chain kinase: pulling the strings of epithelial tight junction function. Ann N Y Acad Sci. 2012;1258:34–42.CrossRefGoogle Scholar
  7. 7.
    Shih DQ, Robert B, Xiaolan Z, et al. Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. PLoS ONE. 2011;6:e16090.CrossRefGoogle Scholar
  8. 8.
    Jørgensen LG, Fredholm L, Hyltoft PP, Hey H, Munkholm P, Brandslund I. How accurate are clinical activity indices for scoring of disease activity in inflammatory bowel disease (IBD)? Clin Chem Lab Med CCLM. 2005;42:403–411.Google Scholar
  9. 9.
    Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–249.Google Scholar
  10. 10.
    Llamas MA, Aller MA, Marquina D, Nava MP, Arias J. Bacterial translocation to mesenteric lymph nodes increases in chronic portal hypertensive rats. Dig Dis Sci. 2010;55:2244–2254.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Buchheister S, Buettner M, Basic M, et al. CD14 plays a protective role in experimental inflammatory bowel disease by enhancing intestinal barrier function. Am J Pathol. 2017;187:1106.CrossRefGoogle Scholar
  13. 13.
    Ye X, Sun M. AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation. Int J Mol Med. 2017;39:1206–1214.CrossRefGoogle Scholar
  14. 14.
    Chang J, Leong RW, Wasinger V, Ip M, Yang M, Giang PT. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. 2017;153:723.CrossRefGoogle Scholar
  15. 15.
    Takeda K, Akira S. Toll-like receptors. In: Current Protocols in Immunology. 2007; Chapter 14:Unit 14.12.Google Scholar
  16. 16.
    Taniguchi K, Wu LW, Grivennikov SI, et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature. 2015;519:57–62.CrossRefGoogle Scholar
  17. 17.
    Amasheh M, Grotjohann I, Amasheh S, et al. Regulation of mucosal structure and barrier function in rat colon exposed to tumor necrosis factor alpha and interferon gamma in vitro: a novel model for studying the pathomechanisms of inflammatory bowel disease cytokines. Scand J Gastroenterol. 2009;44:1226–1235.CrossRefGoogle Scholar
  18. 18.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–680.CrossRefGoogle Scholar
  19. 19.
    Negroni A, Costanzo M, Vitali R, et al. Characterization of adherent-invasive Escherichia coli isolated from pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:913–924.CrossRefGoogle Scholar
  20. 20.
    Ahmad R, Chaturvedi R, Olivares-Villagómez D, et al. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol. 2014;7:1340–1353.CrossRefGoogle Scholar
  21. 21.
    Oshima T, Miwa H, Matsumoto T, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol. 2008;136:A-414-A-414.Google Scholar
  22. 22.
    Du J, Chen Y, Shi Y, et al. 1,25-Dihydroxyvitamin D protects intestinal epithelial barrier by regulating the myosin light chain kinase signaling pathway. Inflamm Bowel Dis. 2015;21:2495.CrossRefGoogle Scholar
  23. 23.
    He F, Peng J, Deng XL, et al. Mechanisms of tumor necrosis factor-alpha-induced leaks in intestine epithelial barrier. Cytokine. 2012;59:264–272.CrossRefGoogle Scholar
  24. 24.
    Boivin MA, Ye D, Kennedy JC, Al-Sadi R, Shepela C, Ma TY. Mechanism of glucocorticoid regulation of the intestinal tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 2007;292:G590.CrossRefGoogle Scholar
  25. 25.
    Barrett R, Zhang X, Koon HW, et al. Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol. 2012;180:636–649.CrossRefGoogle Scholar
  26. 26.
    Negroni A, Costanzo M, Vitali R, et al. Characterization of adherent-invasive Escherichia coli isolated from pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:913–924.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mingyue Yang
    • 1
  • Wenxiu Jia
    • 1
  • Dong Wang
    • 1
  • Fei Han
    • 1
  • Weiwei Niu
    • 1
  • Hong Zhang
    • 1
  • David Q. Shih
    • 2
  • Xiaolan Zhang
    • 1
    Email author
  1. 1.Department of GastroenterologyThe Second Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Cedars-Sinai Inflammatory Bowel and Immunobiology Research InstituteLos AngelesUSA

Personalised recommendations