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Inflammation Research

, Volume 63, Issue 12, pp 1001–1012 | Cite as

Clinical associations between IL-17 family cytokines and periodontitis and potential differential roles for IL-17A and IL-17E in periodontal immunity

  • Raja Azman
  • David F. Lappin
  • Alexandrea MacPherson
  • Marcello Riggio
  • Douglas Robertson
  • Penny Hodge
  • Gordon Ramage
  • Shauna Culshaw
  • Philip M. Preshaw
  • John Taylor
  • Christopher Nile
Original Research Paper

Abstract

Objective

IL-17A is implicated in periodontitis pathogenesis. The roles of IL-17B–IL-17F and IL-17A/F are unknown. This study aimed to determine clinical associations between IL-17 family cytokines and periodontitis and to investigate the biological roles of IL-17A and IL-17E using in vitro model systems.

Materials and methods

Samples from 97 patients with periodontitis and 77 healthy volunteers were used in the study. Serum, saliva and gingival crevicular fluid (GCF) levels of IL-17 family cytokines were measured by ELISA. Oral keratinocytes were stimulated with a P. gingivalis biofilm, or IL-17A, in the presence and absence of IL-17E and the expression of IL-8 and CXCL5 were investigated by ELISA and real-time-PCR. NF-κB phosphorylation in similar experiments was also measured using a cell-based ELISA.

Results

Serum, saliva and GCF IL-17A levels were higher in periodontitis patients and correlated positively with clinical parameters of attachment loss, pocket depth and bleeding on probing. Serum IL-17E levels were lower in periodontitis patients and the serum IL-17A:IL-17E ratio correlated positively with clinical parameters. In vitro, IL-17E inhibited Porphyromonas gingivalis and IL-17A induced expression of chemokines by reducing phosphorylation of the NF-κB p65 subunit.

Conclusions

Serum IL-17A:IL-17E may be a marker of disease severity. IL-17E may have opposing roles to IL-17A in periodontitis pathogenesis. IL-17E can negatively regulate IL-17A and periodontal pathogen induced expression of chemokines by oral keratinocytes.

Keywords

IL-17 IL-25 IL-17E IL-17A Periodontitis IL-8 

Notes

Acknowledgments

We are very grateful to the patients and volunteers who agreed to participate in the study. The project was supported by Funding from Tenovus Scotland (Registered charity number SC009675) and The Oral and Dental Research Trust (Registered charity number 800234).

References

  1. 1.
    Gu C, Wu L, Li X. IL-17 family: cytokines, receptors and signaling. Cytokine. 2013;64(2):477–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Wright JF, Guo Y, Quazi A, et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4 + T cells. J Biol Chem. 2007;282(18):13447–55.PubMedCrossRefGoogle Scholar
  3. 3.
    Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9(8):556–67.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ. Human IL-17: a novel cytokine derived from T cells. J Immunol. 1995;155(12):5483–6.PubMedGoogle Scholar
  5. 5.
    Cardoso CR, Garlet GP, Crippa GE, Rosa AL, Junior WM, Rossi MA, Silva JS. Evidence of the presence of T helper type 17 cells in chronic lesions of human periodontal disease. Oral Microbiol Immunol. 2009;24(1):1–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Adibrad M, Deyhimi P. Ganjalikhani Hakemi M, Behfarnia P, Shahabuei M, Rafiee L. Signs of the presence of Th17 cells in chronic periodontal disease. J Periodontal Res. 2012;47(4):525–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Beklen A, Ainola M, Hukkanen M, Gurgan C, Sorsa T, Konttinen YT. MMPs, IL-1, and TNF are regulated by IL-17 in periodontitis. J Dent Res. 2007;86(4):347–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Konermann A, Beyer M, Deschner J, Allam JP, Novak N, Winter J, Jepsen S, Jager A. Human periodontal ligament cells facilitate leukocyte recruitment and are influenced in their immunomodulatory function by Th17 cytokine release. Cell Immunol. 2012;272(2):137–43.PubMedCrossRefGoogle Scholar
  9. 9.
    Allam JP, Duan Y, Heinemann F, et al. IL-23-producing CD68(+) macrophage-like cells predominate within an IL-17-polarized infiltrate in chronic periodontitis lesions. J Clin Periodontol. 2011;38(10):879–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Honda T, Aoki Y, Takahashi N, et al. Elevated expression of IL-17 and IL-12 genes in chronic inflammatory periodontal disease. Clin Chim Acta. 2008;395(1–2):137–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Duarte PM, da Rocha M, Sampaio E, Mestnik MJ, Feres M, Figueiredo LC, Bastos MF, Faveri M. Serum levels of cytokines in subjects with generalized chronic and aggressive periodontitis before and after non-surgical periodontal therapy: a pilot study. J Periodontol. 2010;81(7):1056–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Schenkein HA, Koertge TE, Brooks CN, Sabatini R, Purkall DE, Tew JG. IL-17 in sera from patients with aggressive periodontitis. J Dent Res. 2010;89(9):943–7.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ozcaka O, Nalbantsoy A, Buduneli N. Interleukin-17 and interleukin-18 levels in saliva and plasma of patients with chronic periodontitis. J Periodontal Res. 2011;46(5):592–8.PubMedGoogle Scholar
  14. 14.
    Vernal R, Dutzan N, Chaparro A, Puente J. Antonieta Valenzuela M, Gamonal J. Levels of interleukin-17 in gingival crevicular fluid and in supernatants of cellular cultures of gingival tissue from patients with chronic periodontitis. J Clin Periodontol. 2005;32(4):383–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Buduneli N, Buduneli E, Kutukculer N. Interleukin-17, RANKL, and osteoprotegerin levels in gingival crevicular fluid from smoking and non-smoking patients with chronic periodontitis during initial periodontal treatment. J Periodontol. 2009;80(8):1274–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Kadkhodazadeh M, Baghani Z, Ebadian AR, Youssefi N, Mehdizadeh AR, Azimi N. IL-17 gene polymorphism is associated with chronic periodontitis and peri-implantitis in Iranian patients: a cross-sectional study. Immunol Invest. 2013;42(2):156–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Correa JD, Madeira MF, Resende RG, et al. Association between polymorphisms in interleukin-17A and -17F genes and chronic periodontal disease. Mediators Inflamm. 2012;2012:846052.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Saraiva AM. Alves e Silva MR, Correia Silva Jde F, da Costa JE, Gollob KJ, Dutra WO, Moreira PR. Evaluation of IL17A expression and of IL17A, IL17F and IL23R gene polymorphisms in Brazilian individuals with periodontitis. Hum Immunol. 2013;74(2):207–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Yu JJ, Ruddy MJ, Wong GC, Sfintescu C, Baker PJ, Smith JB, Evans RT, Gaffen SL. An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals. Blood. 2007;109(9):3794–802.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Eskan MA, Jotwani R, Abe T, et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol. 2012;13(5):465–73.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Koenders MI, Lubberts E, Oppers-Walgreen B, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol. 2005;167(1):141–9.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Koenders MI, Marijnissen RJ, Devesa I, et al. Tumor necrosis factor-interleukin-17 interplay induces S100A8, interleukin-1beta, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: rationale for combination treatment during arthritis. Arthritis Rheum. 2011;63(8):2329–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Iyoda M, Shibata T, Kawaguchi M, Hizawa N, Yamaoka T, Kokubu F, Akizawa T. IL-17A and IL-17F stimulate chemokines via MAPK pathways (ERK1/2 and p38 but not JNK) in mouse cultured mesangial cells: synergy with TNF-alpha and IL-1beta. Am J Physiol Renal Physiol. 2010;298(3):F779–87.PubMedCrossRefGoogle Scholar
  24. 24.
    Kotake S, Yago T, Kawamoto M, Nanke Y. Role of osteoclasts and interleukin-17 in the pathogenesis of rheumatoid arthritis: crucial ‘human osteoclastology’. J Bone Miner Metab. 2012;30(2):125–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Konermann A, Winter J, Novak N, Allam JP, Jager A. Verification of IL-17A and IL-17F in oral tissues and modulation of their expression pattern by steroid hormones. Cell Immunol. 2013;285(1–2):133–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Gumus P, Buduneli E, Biyikoglu B, Aksu K, Sarac F, Nile C, Lappin D, Buduneli N. Gingival crevicular fluid, serum levels of receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, interleukin-17 in rheumatoid arthritis and osteoporosis patients with periodontal disease. J Periodontol. 2013;84(11):1627–37.PubMedGoogle Scholar
  27. 27.
    Ozcaka O, Buduneli N, Ceyhan BO, Akcali A, Hannah V, Nile C, Lappin DF. Is IL-17 involved in the interaction between polycystic ovary syndrome and gingival inflammation? J Periodontol. 2013;83(12):1529–37.CrossRefGoogle Scholar
  28. 28.
    Monteleone G, Pallone F, Macdonald TT. Interleukin-25: a two-edged sword in the control of immune-inflammatory responses. Cytokine Growth Factor Rev. 2010;21(6):471–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Tamachi T, Maezawa Y, Ikeda K, et al. IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice. J Allergy Clin Immunol. 2006;118(3):606–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010;11(3):250–6.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Saenz SA, Noti M, Artis D. Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 2010;31(11):407–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Owyang AM, Zaph C, Wilson EH, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med. 2006;203(4):843–9.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med. 2007;204(1):161–70.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Caruso R, Sarra M, Stolfi C, et al. Interleukin-25 inhibits interleukin-12 production and Th1 cell-driven inflammation in the gut. Gastroenterology. 2009;136(7):2270–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Caruso R, Stolfi C, Sarra M, Rizzo A, Fantini MC, Pallone F, MacDonald TT, Monteleone G. Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase-dependent induction of Socs-3. Blood. 2009;113(15):3512–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Navazesh M. Methods for collecting saliva. Ann N Y Acad Sci. 1993;694:72–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Pratten J, Smith AW, Wilson M. Response of single species biofilms and microcosm dental plaques to pulsing with chlorhexidine. J Antimicrob Chemother. 1998;42(4):453–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Ramage G, Jose A, Coco B, Rajendran R, Rautemaa R, Murray C, Lappin DF, Bagg J. Commercial mouthwashes are more effective than azole antifungals against Candida albicans biofilms in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(4):456–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Sherry L, Millhouse E, Lappin DF, Murray C, Culshaw S, Nile CJ, Ramage G. Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections. BMC Oral Health. 2013;13:47.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Buduneli N, Kinane DF. Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. J Clin Periodontol. 2011;38(Suppl 11):85–105.PubMedCrossRefGoogle Scholar
  42. 42.
    Yamada H. Current perspectives on the role of IL-17 in autoimmune disease. J Inflamm Res. 2010;3:33–44.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Kornman KS, Page RC, Tonetti MS. The host response to the microbial challenge in periodontitis: assembling the players. Periodontology. 2000;1997(14):33–53.Google Scholar
  44. 44.
    Hata K, Andoh A, Shimada M, et al. IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2002;282(6):G1035–44.PubMedGoogle Scholar
  45. 45.
    Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem. 2004;279(53):55633–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Geng H, Wittwer T, Dittrich-Breiholz O, Kracht M, Schmitz ML. Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination. EMBO Rep. 2009;10(4):381–6.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Mattioli I, Sebald A, Bucher C, Charles RP, Nakano HT, Kracht M, Schmitz ML. Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import. J Immunol. 2004;172(10):6336–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Liang SC, Long AJ, Bennett F, et al. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol. 2007;179(11):7791–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuestner RE, Taft DW, Haran A, et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol. 2007;179(8):5462–73.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Raja Azman
    • 1
  • David F. Lappin
    • 1
  • Alexandrea MacPherson
    • 1
  • Marcello Riggio
    • 1
  • Douglas Robertson
    • 1
  • Penny Hodge
    • 1
  • Gordon Ramage
    • 1
  • Shauna Culshaw
    • 1
  • Philip M. Preshaw
    • 2
  • John Taylor
    • 2
  • Christopher Nile
    • 1
  1. 1.Infection and Immunity Research Group, Immunology, Level 9, Dental School, School of Medicine, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
  2. 2.Centre for Oral Health Research and Institute of Cellular MedicineFramlington Place, Newcastle UniversityNewcastle upon TyneEngland, UK

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