Skip to main content
SpringerLink
Log in

Effects of Resveratrol on Tight Junction Proteins and the Notch1 Pathway in an HT-29 Cell Model of Inflammation Induced by Lipopolysaccharide

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Ulcerative colitis (UC) is closely associated with disruption of intestinal epithelial tight junction proteins. A variety of studies have confirmed that resveratrol (RSV), a natural polyphenolic compound, has a potential anti-inflammatory effect and can regulate the expression of tight junction proteins. However, the mechanism by which RSV regulates the expression of tight junction proteins in the intestinal epithelium remains unclear. Therefore, we investigated the potential effect of RSV on tight junction proteins in an HT-29 cell model of inflammation induced by lipopolysaccharide (LPS) and explored its mechanism of action. First, the downregulated expression of the tight junction proteins occludin, ZO-1, and claudin-1 in the HT-29 cell model of inflammation induced by LPS was reversed by incubation with RSV, accompanied by a decrease in the expression of tumor necrosis factor α-converting enzyme (TACE). Additionally, the Notch1 pathway was attenuated and the expression of the inflammatory factors IL-6 and TNF-α was decreased by treatment with RSV. Second, after Jagged-1 was used in combination with RSV to reactivate the Notch1 pathway, the protective effects of RSV against the LPS-induced reductions in the expression of the tight junction proteins occludin, ZO-1, and claudin-1 and the decreases in the levels of the inflammatory factors IL-6 and TNF-α were abolished. These results suggest that RSV might regulate the expression of tight junction proteins by attenuating the Notch1 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

DATA AVAILABILITY

The data that support the findings of this study are available on request from the corresponding author.

References

  1. Kaplan, G.G. 2015. The global burden of IBD: From 2015 to 2025. Nature Reviews. Gastroenterology & Hepatology 1212: 720–727. https://doi.org/10.1038/nrgastro.2015.150.

    Article  Google Scholar 

  2. Porter, R.J., R. Kalla, and G.T Ho. 2020. Ulcerative colitis: recent advances in the understanding of disease pathogenesis. F1000Res 9. https://doi.org/10.12688/f1000research.20805.1.

  3. Schmitz, H., C. Barmeyer, M. Fromm, N. Runkel, H.D. Foss, C.J. Bentzel, E.O. Riecken, and J.R. Dschulzke. 1999. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1162: 301–309. https://doi.org/10.1016/s0016-5085(99)70126-5.

    Article  Google Scholar 

  4. Chelakkot, C., J. Ghim, and S.H. Ryu. 2018. Mechanisms regulating intestinal barrier integrity and its pathological implications. Experimental & Molecular Medicine 508: 1–9. https://doi.org/10.1038/s12276-018-0126-x.

    Article  CAS  Google Scholar 

  5. Ghorbaninejad, M., R. Heydari, P. Mohammadi, S. Shahrokh, M. Haghazali, B. Khanabadi, and A. Meyfour. 2019. Contribution of NOTCH signaling pathway along with TNF-alpha in the intestinal inflammation of ulcerative colitis. Gastroenterol Hepatol Bed Bench 12Suppl1: S80-S86.

  6. Gersemann, M., S. Becker, I.K. Bler, M. Koslowski, G. Wang, K.R. Herrlinger, J. Griger, P. Fritz, K. Fellermann, and M. Schwab. 2009. Differences in goblet cell differentiation between Crohn’s disease and ulcerative colitis. Differentiation 771: 84–94. https://doi.org/10.1016/j.diff.2008.09.008.

    Article  CAS  Google Scholar 

  7. Gordon, W.R., K.L. Arnett, and S.C. Blacklow. 2008. The molecular logic of Notch signaling—a structural and biochemical perspective. J Cell Sci 121Pt 19: 3109–3119. https://doi.org/10.1242/jcs.035683.

  8. Wan, Y., and Z.Q. Yang. 2020. LncRNA NEAT1 affects inflammatory response by targeting miR-129–5p and regulating Notch signaling pathway in epilepsy. Cell Cycle 194: 419–431. https://doi.org/10.1080/15384101.2020.1711578.

  9. Hui, Y., S.G. Yan, and Q. Wang. 2020. Effects of 6-Shogaol on Notch signaling pathway in colonic epithelial cells of ulcerative colitis mice. Zhongguo Ying Yong Sheng Li Xue Za Zhi 361: 90–93. https://doi.org/10.12047/j.cjap.5889.2020.020.

  10. Lin, J.C., J.Q. Wu, F. Wang, F.Y. Tang, J. Sun, B. Xu, M. Jiang, Y. Chu, D. Chen, and X. Li. 2019. QingBai decoction regulates intestinal permeability of dextran sulphate sodium-induced colitis through the modulation of notch and NF-kappaB signalling. Cell Proliferation 522: e12547. https://doi.org/10.1111/cpr.12547.

    Article  CAS  Google Scholar 

  11. Zhao, Y., H. Luan, H. Gao, and X. Wu,Y Zhang, and R. Li. 2020. Gegen Qinlian decoction maintains colonic mucosal homeostasis in acute/chronic ulcerative colitis via bidirectionally modulating dysregulated Notch signaling. Phytomedicine 68: 153182. https://doi.org/10.1016/j.phymed.2020.153182.

    Article  CAS  PubMed  Google Scholar 

  12. Zong, D.D., X.M. Liu, J.H. Li, R.Y. Ouyang, Y.J. Long, P. Chen, and Y. Chen. 2021. Resveratrol attenuates cigarette smoke induced endothelial apoptosis by activating Notch1 signaling mediated autophagy. Respiratory Research 221: 22. https://doi.org/10.1186/s12931-021-01620-3.

    Article  CAS  Google Scholar 

  13. Kim, T.H., J.H. Park, and J.S. WO. 2019. Resveratrol induces cell death through ROS-dependent downregulation of Notch1/PTEN/Akt signaling in ovarian cancer cells. Molecular Medicine Reports 194: 3353–3360. https://doi.org/10.3892/mmr.2019.9962.

    Article  CAS  Google Scholar 

  14. Santos, M.A., F.N. Franco, C.A. Caldeira, G.R.D. Araújo, A. Vieira, and M.M. Chaves. 2021. Antioxidant effect of resveratrol: Change in MAPK cell signaling pathway during the aging process. Archives of Gerontology and Geriatrics 92: 104266. https://doi.org/10.1016/j.archger.2020.104266.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, Q., H. Huang, F. Zheng, H. Liu, F. Qiu, Y. Chen, C. Liang, and Z. Dai. 2020. Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma. Oncoimmunology 91: 1829346. https://doi.org/10.1080/2162402X.2020.1829346.

    Article  Google Scholar 

  16. Salla, M., V. Pandya, K.S. Bhullar, E. Kerek, Y.F. Wong, R. Losch, J. Ou, F.S. Aldawsari, C. Velazquez-Martinez, and A. Thiesen. 2020. Resveratrol and resveratrol-aspirin hybrid compounds as potent intestinal anti-inflammatory and anti-tumor drugs. Molecules 2517. https://doi.org/10.3390/molecules25173849.

  17. Samsamikor, M., N.E. Daryani, P.R. Asl, and H. Azita. 2016. Resveratrol supplementation and oxidative/anti-oxidative status in patients with ulcerative colitis: A randomized, double-blind, placebo-controlled pilot study. Archives of Medical Research 474: 304–309. https://doi.org/10.1016/j.arcmed.2016.07.003.

    Article  CAS  Google Scholar 

  18. Samsamikor, M., N.E. Daryani, P.R. Asl, and H. Azita. 2015. Anti-inflammatory effects of resveratrol in patients with ulcerative colitis: A randomized, double-blind, placebo-controlled pilot study. Archives of Medical Research 464: 280–285. https://doi.org/10.1016/j.arcmed.2015.05.005.

    Article  CAS  Google Scholar 

  19. Zhu, F., J. Zheng, F. Xu, Y. Xi, J. Chen, and X. Xu. 2021. Resveratrol alleviates dextran sulfate sodium-induced acute ulcerative colitis in mice by mediating PI3K/Akt/VEGFA pathway. Frontiers in Pharmacology 12: 693982. https://doi.org/10.3389/fphar.2021.693982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, B., S. Li, X. Sui, L. Guo, X. Liu, H. Li, L. Gao, S. Cai, Y. Li, T. Wang, and X. Piao. 2018. Root extract of Polygonum cuspidatum Siebold & Zucc. ameliorates DSS-induced ulcerative colitis by affecting NF-kappaB signaling pathway in a mouse model via synergistic effects of polydatin, resveratrol, and emodin. Front Pharmacol 9: 347. https://doi.org/10.3389/fphar.2018.00347.

  21. Pan, H.H., X.X. Zhou, Y.Y. Ma, Y.Y. Ma, W.S. Pan, F. Zhao, M.S. Yu, and J.Q. Liu. 2020. Resveratrol alleviates intestinal mucosal barrier dysfunction in dextran sulfate sodium-induced colitis mice by enhancing autophagy. World Journal of Gastroenterology 2633: 4945–4959. https://doi.org/10.3748/wjg.v26.i33.4945.

    Article  CAS  Google Scholar 

  22. Rawat, M., M. Nighot, R. Al-Sadi, Y. Gupta, D. Viszwapriya, G. Yochum, W. Koltun, and T.Y. Ma. 2020. IL1B increases intestinal tight junction permeability by up-regulation of MIR200C-3p, which degrades occludin mRNA. Gastroenterology 1594: 1375–1389. https://doi.org/10.1053/j.gastro.2020.06.038.

    Article  CAS  Google Scholar 

  23. Pochard, C., J. Gonzales, A. Bessard, M.M. Mahe, A. Bourreille, N. Cenac, A. Jarry, E. Coron, J. Podevin, and G. Meurette. 2021. PGI2 inhibits intestinal epithelial permeability and apoptosis to alleviate colitis. Cellular and Molecular Gastroenterology and Hepatology 123: 1037–1060. https://doi.org/10.1016/j.jcmgh.2021.05.001.

    Article  CAS  Google Scholar 

  24. Ma, Y., J. Yue, Y. Zhang, C. Shi, M. Odenwald, W.G. Liang, Q. Wei, A. Goel, X. Gou, and J. Zhang. 2017. ACF7 regulates inflammatory colitis and intestinal wound response by orchestrating tight junction dynamics. Nature Communications 8: 15375. https://doi.org/10.1038/ncomms15375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mayangsari, Y., and T. Suzuki. 2018. Resveratrol ameliorates intestinal barrier defects and inflammation in colitic mice and intestinal cells. Journal of Agricultural and Food Chemistry 6648: 12666–12674. https://doi.org/10.1021/acs.jafc.8b04138.

    Article  CAS  Google Scholar 

  26. Brynskov, J., P. Foegh, G. Pedersen, C. Ellervik, T. Kirkegaard, A. Bingham, and T. Saermark. 2002. Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut 511: 37–43. https://doi.org/10.1136/gut.51.1.37.

    Article  Google Scholar 

  27. Yamamoto-Furusho, J.K., E.J. Mendivil-Rangel, and B.G. Fonseca-Camarillo. 2012. Differential expression of occludin in patients with ulcerative colitis and healthy controls. Inflammatory Bowel Diseases 1810: E1999. https://doi.org/10.1002/ibd.22835.

    Article  Google Scholar 

  28. Mathern, D., L. Laitman, Z. Hovhannisyan, D. Dunkin, S. Farsio, T. Malik, G. Roda, A. Chitre, A. Iuga, and G. Yeretssian. 2014. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunology 74: 995–1005. https://doi.org/10.1038/mi.2013.118.

    Article  CAS  Google Scholar 

  29. Kopan, R., and M.X.G. Ilagan. 2009. The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell 1372: 216–233. https://doi.org/10.1016/j.cell.2009.03.045.

    Article  CAS  Google Scholar 

  30. Zhang, Q., C. Wang, Z. Liu, X. Liu, C. Han, X. Cao, and N. Li. 2012. Notch signal suppresses Toll-like receptor-triggered inflammatory responses in macrophages by inhibiting extracellular signal-regulated kinase 1/2-mediated nuclear factor kappaB activation. Journal of Biological Chemistry 2879: 6208–6217. https://doi.org/10.1074/jbc.M111.310375.

    Article  CAS  Google Scholar 

  31. Alvarado, D.M., B. Chen, M. Iticovici, A.I. Thaker, N. Dai, K.L. VanDussen, N. Shaikh, C.K. Lim, G.J. Guillemin, P.I. Tarr, and M.A. Ciorba. 2019. Epithelial indoleamine 2,3-dioxygenase 1 modulates aryl hydrocarbon receptor and notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota. Gastroenterology 1574 (1093–1108): e1011. https://doi.org/10.1053/j.gastro.2019.07.013.

    Article  CAS  Google Scholar 

  32. Cong, Z., G. Ye, Z. Bian, M.H. Yu, and M. Zhong. 2018. Jagged-1 attenuates LPS-induced apoptosis and ROS in rat intestinal epithelial cells. International Journal of Clinical and Experimental Pathology 118: 3994–4003.

    Google Scholar 

Download references

Funding

This work was financially supported by a grant from the National Natural Science Foundation of China (81,660,093).

Author information

Authors and Affiliations

  1. Department of Gerontology and Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China

    Yihua Luo, Xueyan Yu, Peizhuang Zhao, Jun Huang & Xue Huang

Authors
  1. Yihua Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueyan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peizhuang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xue Huang contributed to the conception of the paper and reviewed the final manuscript. Yihua Luo performed most of the experiments described in the manuscript and wrote the paper. Xueyan Yu performed the data analysis. Peizhuang Zhao and Jun Huang contributed to constructive discussions.

Corresponding author

Correspondence to Xue Huang.

Ethics declarations

Ethical Approval

Not applicable.

Consent for Publication

All authors have read and approved the submission

Competing Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, Y., Yu, X., Zhao, P. et al. Effects of Resveratrol on Tight Junction Proteins and the Notch1 Pathway in an HT-29 Cell Model of Inflammation Induced by Lipopolysaccharide. Inflammation 45, 2449–2464 (2022). https://doi.org/10.1007/s10753-022-01704-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-022-01704-2

KEY WORDS

Search

Navigation