, Volume 38, Issue 4, pp 1683–1689 | Cite as

The Activation of NF-κB in Infiltrated Mononuclear Cells Negatively Correlates with Treg Cell Frequency in Oral Lichen Planus

  • Dunfang Zhang
  • Jiayi Wang
  • Zhangwei Li
  • Min Zhou
  • Qianming Chen
  • Xin ZengEmail author
  • Yu ChenEmail author


Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease with persistent accumulation of T cells in the lamina propria. Nuclear factor-kappa B (NF-κB) is a major regulator of immune responses, and NF-κB-dependent cytokines and pro-inflammatory mediators can be detected in higher levels in the saliva and serum from patients with OLP. CD4+CD25+Foxp3+ regulatory T (Treg) cells play an important role in the prevention of autoimmune pathology by regulating the immune response. To explore the correlation between NF-κB p65 activation and accumulation of Treg cells in patients with OLP, 40 ethnic Chinese patients with OLP and 10 healthy volunteers were recruited. The nuclear expression of NF-κB p65 in infiltrated mononuclear cells and Treg cells in the OLP lesion and the normal oral mucosa (NOM) was analyzed by immunohistochemistry assay. Our results showed that both the nuclear expression of NF-κB p65 and the number of Foxp3+ Treg were higher in the OLP lesions. Furthermore, the frequency of Treg cells was negatively correlated with NF-κB nuclear expression in subepithelial lymphocytic infiltrate of the OLP lesion. This finding provides a new insight into the pathogenesis of OLP and may contribute to novel therapeutic strategies for the treatment of OLP by modulating the immune system.


OLP Foxp3 NF-κB inflammation immunotherapy 



We are particularly grateful to Dr. Eric Tu from the National Institute of Dental and Craniofacial Research (NIDCR/NIH, USA) for critical reading and suggestions for the manuscript. We thank the 111 Project of MOE & ISTCPC (2012DFA31370), China; and the National Natural Science Foundation of China (document no.: 81321002, 81472533 and 81400525)

Compliance with Ethical Standards

The authors declare that there is no potential conflict of interest. This study was approved by the Department of Oral Medicine, West China Hospital of Stomatology of Sichuan University, and the Committee for the Use of Human Subjects in Research in Sichuan University, with informed consent by all human participants involved in this study.


  1. 1.
    Santoro, A., A. Majorana, E. Bardellini, S. Festa, P. Sapelli, and F. Facchetti. 2003. NF-kappaB expression in oral and cutaneous lichen planus. Journal of Pathology 201: 466–472.PubMedCrossRefGoogle Scholar
  2. 2.
    Wu, R.Q., D.F. Zhang, E. Tu, Q.M. Chen, and W. Chen. 2014. The mucosal immune system in the oral cavity-an orchestra of T cell diversity. International Journal of Oral Science 6: 125–132.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Simark Mattsson, C., M. Jontell, G. Bergenholtz, M. Heyden, and U.I. Dahlgren. 1998. Distribution of interferon-gamma mRNA-positive cells in oral lichen planus lesions. Journal of Oral Pathology & Medicine 27: 483–488.CrossRefGoogle Scholar
  4. 4.
    Zhang, Y., W. Liu, S. Zhang, H. Dan, R. Lu, F. Wang, J. Wang, M. Zhou, X. Zeng, M. Lin, et al. 2012. Salivary and serum interleukin-18 in patients with oral lichen planus: A study in an ethnic Chinese population. Inflammation 35: 399–404.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhou, G., K. Xia, G.F. Du, X.M. Chen, X.Y. Xu, R. Lu, and H.M. Zhou. 2009. Activation of nuclear factor-kappa B correlates with tumor necrosis factor-alpha in oral lichen planus: A clinicopathologic study in atrophic-erosive and reticular form. Journal of Oral Pathology & Medicine 38: 559–564.CrossRefGoogle Scholar
  6. 6.
    Dan, H., W. Liu, Y. Zhou, J. Wang, Q. Chen, and X. Zeng. 2010. Association of interleukin-8 gene polymorphisms and haplotypes with oral lichen planus in a Chinese population. Inflammation 33: 76–81.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang, H., Q. Han, Z. Luo, C. Xu, J. Liu, H. Dan, Y. Xu, X. Zeng, and Q. Chen. 2014. Oral lichen planus may enhance the expression of Th17-associated cytokines in local lesions of chronic periodontitis. Clinical Oral Investigations 18: 1647–1654.PubMedCrossRefGoogle Scholar
  8. 8.
    Nico, M.F.J., and S.V. Lourenço. 2011. Oral lichen planus. Anais Brasileiros De Dermatologia 86: 633–643.PubMedCrossRefGoogle Scholar
  9. 9.
    Liu, W.Z., M.J. He, L. Long, D.L. Mu, M.S. Xu, X. Xing, X. Zeng, G. Liao, H.X. Dan, and Q.M. Chen. 2014. Interferon-gamma and interleukin-4 detected in serum and saliva from patients with oral lichen planus. International Journal of Oral Science 6: 22–26.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lodi, G.M.C., S. Furness, and K. Thongpraso. 2012. Interventions for treating oral lichen planus: A systematic review. British Journal of Dermatology 166: 938–947.PubMedCrossRefGoogle Scholar
  11. 11.
    Lu, R., X. Zeng, Q. Han, M. Lin, L. Long, H. Dan, G. Zhou, and Q. Chen. 2014. Overexpression and selectively regulatory roles of IL-23/IL-17 axis in the lesions of oral lichen planus. Mediators of Inflammation 2014: 701094.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Chen, J., J. Feng, X. Chen, H. Xu, Z. Zhou, X. Shen, Z. Bao, W. Liu, and Z. Shen. 2013. Immunoexpression of interleukin-22 and interleukin-23 in oral and cutaneous lichen planus lesions: A preliminary study. Mediators of Inflammation 2013: 801974.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Ge, Y., Y. Xu, W. Sun, Z. Man, L. Zhu, X. Xia, L. Zhao, Y. Zhao, and X. Wang. 2012. The molecular mechanisms of the effect of dexamethasone and cyclosporin A on TLR4/NF-kappaB signaling pathway activation in oral lichen planus. Gene 508: 157–164.PubMedCrossRefGoogle Scholar
  14. 14.
    Kaufman, M.B. 1994. Adverse effects associated with dexamethasone, lorazepam, and granisetron. Annals of Pharmacotherapy 28: 1306–1307.PubMedGoogle Scholar
  15. 15.
    Moynagh, P.N. 2005. The NF-kappaB pathway. Journal of Cell Science 118: 4589–4592.PubMedCrossRefGoogle Scholar
  16. 16.
    Hayden, M.S., and S. Ghosh. 2008. Shared principles in NF-kappaB signaling. Cell 132: 344–362.PubMedCrossRefGoogle Scholar
  17. 17.
    Gilmore, T.D. 2006. Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene 25: 6680–6684.PubMedCrossRefGoogle Scholar
  18. 18.
    Gerondakis, S., T.S. Fulford, N.L. Messina, and R.J. Grumont. 2014. NF-kappaB control of T cell development. Nature Immunology 15: 15–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoffmann, A., G. Natoli, and G. Ghosh. 2006. Transcriptional regulation via the NF-kappaB signaling module. Oncogene 25: 6706–6716.PubMedCrossRefGoogle Scholar
  20. 20.
    Rhodus, N.L., B. Cheng, S. Myers, W. Bowles, V. Ho, and F. Ondrey. 2005. A comparison of the pro-inflammatory, NF-kappaB-dependent cytokines: TNF-alpha, IL-1-alpha, IL-6, and IL-8 in different oral fluids from oral lichen planus patients. Clinical Immunology 114: 278–283.PubMedCrossRefGoogle Scholar
  21. 21.
    Rhodus, N.L., B. Cheng, S. Myers, L. Miller, V. Ho, and F. Ondrey. 2005. The feasibility of monitoring NF-kappaB associated cytokines: TNF-alpha, IL-1alpha, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus. Molecular Carcinogenesis 44: 77–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang, Y., M. Lin, S. Zhang, Z. Wang, L. Jiang, J. Shen, J. Bai, F. Gao, M. Zhou, and Q. Chen. 2008. NF-kappaB-dependent cytokines in saliva and serum from patients with oral lichen planus: A study in an ethnic Chinese population. Cytokine 41: 144–149.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen, W. 2011. Tregs in immunotherapy: Opportunities and challenges. Immunotherapy 3: 911–914.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen, W., and J.E. Konkel. 2010. TGF-beta and ‘adaptive’ Foxp3(+) regulatory T cells. Journal of Molecular Cell Biology 2: 30–36.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Tarbell, K.V., L. Petit, X. Zuo, P. Toy, X. Luo, A. Mqadmi, H. Yang, M. Suthanthiran, S. Mojsov, and R.M. Steinman. 2007. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. The Journal of Experimental Medicine 204: 191–201.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Tang, Q., K.J. Henriksen, M. Bi, E.B. Finger, G. Szot, J. Ye, E.L. Masteller, H. McDevitt, M. Bonyhadi, and J.A. Bluestone. 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. The Journal of Experimental Medicine 199: 1455–1465.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Webster, K.E., S. Walters, R.E. Kohler, T. Mrkvan, O. Boyman, C.D. Surh, S.T. Grey, and J. Sprent. 2009. In vivo expansion of T reg cells with IL-2-mAb complexes: Induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. The Journal of Experimental Medicine 206: 751–760.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kasagi S, Zhang P, Che L, Abbatiello B, Maruyama T, Nakatsukasa H, Zanvit P, Jin W, Konkel JE, Chen W. 2014. In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Science Translational Medicine 6: 241ra278.Google Scholar
  29. 29.
    Tu, E., D. Bourges, P.A. Gleeson, D.K. Ang, and I.R. van Driel. 2013. Pathogenic T cells persist after reversal of autoimmune disease by immunosuppression with regulatory T cells. European Journal of Immunology 43: 1286–1296.PubMedCrossRefGoogle Scholar
  30. 30.
    Morgan, M.E., R. Flierman, L.M. van Duivenvoorde, H.J. Witteveen, W. van Ewijk, J.M. van Laar, R.R. de Vries, and R.E. Toes. 2005. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis and Rheumatism 52: 2212–2221.PubMedCrossRefGoogle Scholar
  31. 31.
    van der Meij, E.H., K.-P. Schepman, and I. van der Waal. 2003. The possible premalignant character of oral lichen planus and oral lichenoid lesions: A prospective study. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 96: 164–171.PubMedCrossRefGoogle Scholar
  32. 32.
    van der Meij, E.H., H. Mast, and I. van der Waal. 2007. The possible premalignant character of oral lichen planus and oral lichenoid lesions: A prospective five-year follow-up study of 192 patients. Oral Oncology 43: 742–748.PubMedCrossRefGoogle Scholar
  33. 33.
    Anne, E., E.T. Goldfeld, Randall Kincaid, Peter J. Belshaw, Stuart L. Schrieber, Jack L. Strominger, and Anjana Rao. 1994. Calcineurin mediates human tumor necrosis factor alpha gene induction in stimulated T and B cells. The Journal of Experimental Medicine 180: 763–768.CrossRefGoogle Scholar
  34. 34.
    Nishimura, K.N.N., E. Satoh, Y. Harada, M. Nakayama, T. Tokizane, T. Fukui, Y. Ono, H. Inoue, M. Shin, Y. Tsujimoto, H. Takayama, K. Aozasa, and A. Okuyama. 2001. Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. Journal of the National Cancer Institute 93: 1739–1746.PubMedCrossRefGoogle Scholar
  35. 35.
    Lozada-Nur, F., and C. Miranda. 1997. Oral lichen planus: Topical and systemic therapy. Seminars in Cutaneous Medicine and Surgery 16: 295–300.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhu, Y., J. Li, Y. Bai, X. Wang, N. Duan, H. Jiang, T. Wang, and W. Wang. 2014. Hydroxychloroquine decreases the upregulated frequencies of Tregs in patients with oral lichen planus. Clinical Oral Investigations 18: 1903–1911.PubMedCrossRefGoogle Scholar
  37. 37.
    Tao, X.A., J. Xia, X.B. Chen, H. Wang, Y.H. Dai, N.L. Rhodus, and B. Cheng. 2010. FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity. Oral Diseases 16: 76–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.State Key Laboratory of Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduChina
  2. 2.Department of Stomatologythe First Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhouChina
  3. 3.Department of Oral Pathology, West China Hospital of StomatologySichuan UniversityChengduChina

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