Skip to main content

Advertisement

SpringerLink
Log in

Interleukin (IL)-35 Suppresses IL-6 and IL-8 Production in IL-17A-Stimulated Human Periodontal Ligament Cells

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Interleukin (IL)-35 is a novel anti-inflammatory cytokine that is produced by regulatory T cells. IL-35 is reported to suppress IL-17A-producing helper T (Th17) cell activation. IL-17A is related to progression of periodontitis. Furthermore, IL-35 and IL-17A are detected in human gingival crevicular fluid. However, the effect of IL-35 and interaction between IL-35 and IL-17A on pro-inflammatory cytokine production in human periodontal resident cells are still unclear. The aim of this study was to clarify the effect of IL-35 on IL-6 and IL-8 production in human periodontal ligament cells (HPDLCs) stimulated with IL-17A. IL-35 inhibited IL-6 and IL-8 production in IL-17A-stimulated HPDLCs. Moreover, western blot analysis showed that IL-35 suppressed extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-κB p65 phosphorylation in IL-17A-stimulated HPDLCs. Our findings suggested that IL-35 produced from regulatory T cells might inhibit progression of periodontitis by decreasing IL-17A-induced levels of IL-6 and IL-8.

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

Similar content being viewed by others

References

  1. Taubman, M.A., H. Yoshie, J.L. Ebersole, D.J. Smith, and C.L. Olson. 1984. Host response in experimental periodontal disease. Journal of Dental Research 63: 455–460.

    Article  CAS  Google Scholar 

  2. Cardoso, C.R., G.P. Garlet, G.E. Crippa, A.L. Rosa, W.M. Júnior, M.A. Rossi, and J.S. Silva. 2009. Evidence of the presence of T helper type 17 cells in chronic lesions of human periodontal disease. Oral Microbiology and Immunology 24: 1–6.

    Article  CAS  Google Scholar 

  3. Kotake, S., N. Udagawa, N. Takahashi, K. Matsuzaki, K. Itoh, S. Ishiyama, S. Saito, K. Inoue, N. Kamatani, M.T. Gillespie, T.J. Martin, and T. Suda. 1999. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. Journal of Clinical Investigation 103: 1345–1352.

    Article  CAS  Google Scholar 

  4. Shibata, M., Y. Shintaku, K. Matsuzaki, and S. Uematsu. 2014. The effect of IL-17 on the production of proinflammatory cytokines and matrix metalloproteinase-1 by human periodontal ligament fibroblasts. Orthodontics & Craniofacial Research 17 (1): 60–68.

    Article  CAS  Google Scholar 

  5. Bendtzen, K. 1988. Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. Immunology Letters 19: 183–191.

    Article  CAS  Google Scholar 

  6. Hashizume, M., N. Hayakawa, and M. Mihara. 2008. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology 47: 1635–1640.

    Article  CAS  Google Scholar 

  7. Bettelli, E., Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, and V.K. Kuchroo. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235–238.

    Article  CAS  Google Scholar 

  8. Fredriksson, M., K. Bergström, and B. Asman. 2002. IL-8 and TNF-alpha from peripheral neutrophils and acute-phase proteins in periodontitis. Journal of Clinical Periodontology 29: 123–128.

    Article  CAS  Google Scholar 

  9. Devergne, O., M. Birkenbach, and E. Kieff. 1997. Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proceedings of the National Academy of Sciences 94: 12041–12046.

    Article  CAS  Google Scholar 

  10. Collison, L.W., C.J. Workman, T.T. Kuo, K. Boyd, Y. Wang, K.M. Vignali, R. Cross, D. Sehy, R.S. Blumberg, and D.A. Vignali. 2007. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450: 566–569.

    Article  CAS  Google Scholar 

  11. Shen, P., T. Roch, V. Lampropoulou, R.A. O'Connor, U. Stervbo, E. Hilgenberg, S. Ries, V.D. Dang, Y. Jaimes, C. Daridon, R. Li, L. Jouneau, P. Boudinot, S. Wilantri, I. Sakwa, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, K. Hoehlig, E. Meinl, A. Grützkau, J.R. Grün, K. Horn, A.A. Kühl, T. Dörner, A. Bar-Or, S.H.E. Kaufmann, S.M. Anderton, and S. Fillatreau. 2014. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507: 366–370.

    Article  CAS  Google Scholar 

  12. Olson, B.M., E. Jankowska-Gan, J.T. Becker, D.A. Vignali, W.J. Burlingham, and D.G. McNeel. 2012. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. Journal of Immunology 189: 5590–5601.

    Article  CAS  Google Scholar 

  13. Okada, K., T. Fujimura, T. Kikuchi, M. Aino, Y. Kamiya, A. Izawa, Y. Iwamura, H. Goto, I. Okabe, E. Miyake, Y. Hasegawa, M. Mogi, and A. Mitani. 2017. Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4+ T cells. PeerJ 5: e2999.

    Article  Google Scholar 

  14. Wang, R.X., C.R. Yu, R.M. Mahdi, and C.E. Egwuagu. 2012. Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells. Journal of Biological Chemistry 287: 36012–36021.

    Article  CAS  Google Scholar 

  15. Thiolat, A., A. Denys, M. Petit, J. Biton, D. Lemeiter, R. Herve, D. Lutomski, M.C. Boissier, and N. Bessis. 2014. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine 69: 87–93.

    Article  CAS  Google Scholar 

  16. Mitani, A., W. Niedbala, T. Fujimura, M. Mogi, S. Miyamae, N. Higuchi, A. Abe, T. Hishikawa, M. Mizutani, Y. Ishihara, H. Nakamura, K. Kurita, N. Ohno, Y. Tanaka, M. Hattori, and T. Noguchi. 2015. Increased expression of interleukin (IL)-35 and IL-17, but not IL-27, in gingival tissues with chronic periodontitis. Journal of Periodontology 86: 301–309.

    Article  CAS  Google Scholar 

  17. Shindo, S., Y. Hosokawa, I. Hosokawa, K. Ozaki, and T. Matsuo. 2014. Genipin inhibits IL-1β-induced CCL20 and IL-6 production from human periodontal ligament cells. Cellular Physiology and Biochemistry 33: 357–364.

    Article  CAS  Google Scholar 

  18. Jung, Y.J., Y.J. Choi, S.J. An, H.R. Lee, H.K. Jun, and B.K. Choi. 2017. Tannerella forsythia GroEL induces inflammatory bone resorption and synergizes with interleukin-17. Molecular Oral Microbiology 32: 301–313.

    Article  CAS  Google Scholar 

  19. Köseoğlu, S., M. Sağlam, T. Pekbağrıyanık, L. Savran, and R. Sütçü. 2015. Level of interleukin-35 in gingival crevicular fluid, saliva, and plasma in periodontal disease and health. Journal of Periodontology 24: 1–6.

    Google Scholar 

  20. Wilson, N.J., K. Boniface, J.R. Chan, B.S. McKenzie, W.M. Blumenschein, J.D. Mattson, B. Basham, K. Smith, T. Chen, F. Morel, J.C. Lecron, R.A. Kastelein, D.J. Cua, T.K. McClanahan, E.P. Bowman, and Malefyt R. de Waal. 2007. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunology 8: 950–957.

    Article  CAS  Google Scholar 

  21. Takahashi, K., T. Azuma, H. Motohira, D.F. Kinane, and S. Kitetsu. 2005. The potential role of interleukin-17 in the immunopathology of periodontal disease. Journal of Clinical Periodontology 32: 369–374.

    Article  CAS  Google Scholar 

  22. Lin, D., L. Li, Y. Sun, W. Wang, X. Wang, Y. Ye, X. Chen, and Y. Xu. 2014. IL-17 regulates the expressions of RANKL and OPG in human periodontal ligament cells via TRAF6/TBK1-JNK/NF-κB pathways. Immunology 144: 472–485.

    Article  Google Scholar 

  23. Wu, Y., L. Zhu, L. Liu, J. Zhang, and B. Peng. 2014. Interleukin-17A stimulates migration of periodontal ligament fibroblasts via p38 MAPK/NF-κB-dependent MMP-1 expression. Journal of Cellular Physiology 229: 292–299.

    Article  CAS  Google Scholar 

  24. Wang, Y., Y. Mao, J. Zhang, G. Shi, L. Cheng, Y. Lin, Y. Li, X. Zhang, Y. Zhang, X. Chen, J. Deng, X. Su, L. Dai, Y. Yang, S. Zhang, D. Yu, Y. Wei, and H. Deng. 2018. IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells. Journal of Cellular and Molecular Medicine 22: 1014–1025.

    CAS  PubMed  Google Scholar 

  25. Zhang, X.H., Y. Zhou, J.M. Zhang, S.Y. Zhou, M. Wang, R. Feng, F.E. Feng, Q.M. Wang, X.L. Zhu, X.S. Zhao, M. Lv, Y. Kong, Y.J. Chang, and X.J. Huang. 2015. IL-35 inhibits acute graft-versus-host disease in a mouse model. International Immunopharmacology 29: 383–392.

    Article  CAS  Google Scholar 

  26. Wu, S., Y. Li, Y. Li, L. Yao, T. Lin, S. Jiang, H. Shen, L. Xia, and J. Lu. 2016. Interleukin-35 attenuates collagen-induced arthritis through suppression of vascular endothelial growth factor and its receptors. International Immunopharmacology 34: 71–77.

    Article  CAS  Google Scholar 

  27. Hu, L., C. Chen, J. Zhang, K. Wu, X. Zhang, H. Liu, and J. Hou. 2017. IL-35 pretreatment alleviates lipopolysaccharide-induced acute kidney injury in mice by inhibiting NF-κB activation. Inflammation 40: 1393–1400.

    Article  CAS  Google Scholar 

  28. Chen, X., S. Hao, Z. Zhao, J. Liu, Q. Shao, F. Wang, D. Sun, Y. He, W. Gao, and H. Mao. 2018. Interleukin 35: inhibitory regulator in monocyte-derived dendritic cell maturation and activation. Cytokine 108: 43–52.

    Article  CAS  Google Scholar 

  29. Sha, X., S. Meng, X. Li, H. Xi, M. Maddaloni, D.W. Pascual, H. Shan, X. Jiang, H. Wang, and X.F. Yang. 2015. Interleukin-35 inhibits endothelial cell activation by suppressing MAPK-AP-1 pathway. Journal of Biological Chemistry 290: 19307–19318.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by Grants-in-Aid for Young Scientists (Start-up) from the Japan Society for the Promotion of Science KAKENHI (Grant No. JP17H06896).

Author information

Authors and Affiliations

  1. Department of Biological Endodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan

    Satoru Shindo & Hideki Shiba

  2. Department of Conservative Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, Tokushima, 770-8504, Japan

    Yoshitaka Hosokawa & Ikuko Hosokawa

Authors
  1. Satoru Shindo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshitaka Hosokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ikuko Hosokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideki Shiba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoru Shindo.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

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

Shindo, S., Hosokawa, Y., Hosokawa, I. et al. Interleukin (IL)-35 Suppresses IL-6 and IL-8 Production in IL-17A-Stimulated Human Periodontal Ligament Cells. Inflammation 42, 835–840 (2019). https://doi.org/10.1007/s10753-018-0938-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-018-0938-9

KEY WORDS

Search

Navigation