The interleukin-1 receptor antagonist (IL-1-Ra) and soluble tumor necrosis factor receptor I (sTNF RI) in periodontal disease


The course and severity of periodontitis can be significantly affected by bacterial virulence as well as host immunity dysfunction. Periodontal tissue destruction has been proved to result from cascade of cytokines synthesized by reactive cells upon stimulation by pathogenic bacteria and lipopolysaccharides within their cell membranes. The clinical use of genetically programmed cells, producing substances blocking IL-1, based on recombinant IL-1 antagonist, as well as cytokines activating fibroblasts and osteoblasts to regenerate the destroyed periodontal tissue could prove alternative to the conventional treatment. Another cytokine of interest in respect to periodontitis ethiopathogenesis is soluble tumor necrosis factor receptor I (sTNF RI). Observation of soluble TNF receptors as physiologic inhibitors of TNF led to its administration in therapeutic process as well as in therapy selected cases of aggressive periodontitis.

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Slotwinska, S. (2013) The interleukin-1 receptor antagonist (IL-1-Ra) and soluble tumor necrosis factor receptor I (sTNF RI) in periodontal disease. Open Journal of Immunology, 3, 10-16. doi: 10.4236/oji.2013.31002.

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The authors declare no conflicts of interest.


[1] Gemmell, E., Marshall, R.I., Seymour, G.J. (1997) Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease. Periodontology, 14, 112-143. doi:10.1111/j.1600-0757.1997.tb00194.x
[2] Deo, V. and Bhongade, M.L. (2010) Pathogenesis of periodontitis: Role of cytokines in host response. Dent Today, 29, 60-69.
[3] Kobayashi, T., Murasawa, A., Kumatsu, Y., Yokoyama, T., Ishida, K., Abe, A., Yamamoto, K. and Yoshie, H. (2010) Serum cytokine and periodontal profiles in relation to disease activity of rheumatoid arthritis in Japanese adults. Journal of Periodontology, 81, 650-657. doi:10.1902/jop.2010.090688
[4] Taylor, J.J. (2010) Cytokine regulation of immune responses to Porphyromonas gingivalis. Periodontology, 54, 160-194. doi:10.1111/j.1600-0757.2009.00344.x
[5] Rawlinson, A., Dalati, M.H., Rahman, S., Walsh, T.F. and Fairclough, A.L. (2000) Interleukin-1 and IL-1 receptor antagonist in gingival crevicular fluid. Journal of Periodontology, 27, 738-743. doi:10.1034/j.1600-051x.2000.027010738.x
[6] Toker, H., Poyraz, O. and Eren, K. (2008) Effect of periodontal treatment on IL-1 beta, IL-1 ra, and IL-10 levels in gingival crevicular fluid in patients with aggressive periodontitis. Journal of Periodontology, 35, 507-513. doi:10.1111/j.1600-051X.2008.01213.x
[7] Cairo, F., Nieri, M., Gori, A.M., Tonelli, P., Branchi, R., Castellani, S., Abbate, R. and Pini-Prato, G.P. (2010) Markers of systemic inflammation in periodontal patients: Chronic versus aggressive periodontitis. An explorative cross-sectional study. European Journal of Oral Implantology, 3, 147-153.
[8] Trevilatto, P.C., de Souza Pardo, A.P., Scarel-Caminaga, R.M., de Brito, R.B. Jr, Alvim-Pereira, F., Alvim-Pereira, C.C., Probst, C.M., Garlet, G.P., Sallum, A.W. and Line, S.R. (2011) Association of IL-1 gene polymorphism with chronic periodontitis in Brazilians. Archives of Oral Biology, 56, 54-62. doi:10.1016/j.archoralbio.2010.09.004
[9] Tatakis, D.N. (1993) Interleukin-1 and bone metabolism: A review. Journal of Periodontology, 64, 416-431.
[10] Rose-John, S. and Heinrich, P.C. (1994) Soluble receptors for cytokines and growth factors: Generation and biological function. Biochemical Journal, 300, 281-290.
[11] Arend, W.P. (1993) Interleukin-1 receptor antagonist. Advances in Immunology, 54, 167-227. doi:10.1016/S0065-2776(08)60535-0
[12] Colotta, F., Ghezzi, P. and Mantovani, A. (1998) Interleukin-1. Cytokines, 1-18. doi:10.1016/B978-012498340-3/50002-6
[13] Dinarello, C.A. (1991) Interleukin-1 and interleukin-1 antagonism. Blood, 77, 1627-1652.
[14] Yoshimura, A., Hara, Y., Kaneko, T. and Kato, I. (1997) Secretion of IL-1β, TNF-α, IL-8 and IL-ra by human polymorphonuclear leukocytes in response to lipopolysaccharides from periodontopathic bacteria. Journal of Periodontal Research, 32, 279-286. doi:10.1111/j.1600-0765.1997.tb00535.x
[15] Re, F., Mengozzi, M., Muzio, M., Dinarello, C.A., Mantovani, A. and Colotta, F. (1993) Expression of interleukin-1 receptor antagonist (IL-1ra) by human circulating polymorphonuclear cells. European Journal of Immunology, 23, 570-573. doi:10.1002/eji.1830230242
[16] Rambaldi, A., Torcia, M., Bettoni, S., Vannier, E., Barbui, T., Shaw, A.R., Dinarello, C.A. and Cozzolino, F. (1991) Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin-1 receptor antagonist and lack of its expression by leukemic cells. Blood, 78, 3248-3253.
[17] Cominelli, F., Nast, C.C., Clark, B.D., Schindler, R., Lierena, R., Eysselein, V.E., Thompson, R.C. and Dinarello, C.A. (1990) Interleukin-1 gene expression, synthesis and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. Journal of Clinical Investigation, 86, 972-980. doi:10.1172/JCI114799
[18] Ohlsson, K., Bjork, P., Bergenfeldt, M., Hageman, R. and Thompson, R.C. (1990) Interleukin-1 receptor antagonist reduced mortality from endotoxin shock. Nature, 348, 550-552. doi:10.1038/348550a0
[19] Tsai, C.C., Ho, Y.P. and Chen, C.C. (1995) Levels of inter-leukin-1β and interleukin-8 in gingival cervicular fluids in adults periodontitis. Journal of Periodontology, 66, 852-859. doi:10.1902/jop.1995.66.10.852
[20] Boch, J.A., Wara-aswapati, N. and Auron, P.E. (2001) Inter-leukin 1 signal transduction-current concepts and relevance to periodontitis. Journal of Dental Research, 80, 400-407. doi:10.1177/00220345010800020101
[21] Zambon, J.J. (1985) Actinobacillus actinomycetemcomitans in human periodontal disease. Journal of Periodontology, 12, 1-20. doi:10.1111/j.1600-051X.1985.tb01348.x
[22] Page, R.C. (1991) The role of inflammatory mediators in the pathogenesis of periodontal disease. Journal of Periodontal Research, 26, 230-242. doi:10.1111/j.1600-0765.1991.tb01649.x
[23] Sims, T.J., Moncla, B.J., Darveau, R.P. and Page, R.C. (1991) Antigens of Actinobacillus actinomycetemcomitans recognized by patients with juvenile periodontitis and periodontally normal subjects. Infection and Immunity, 59, 913-924.
[24] Granowitz, E.V., Clark, B.D., Vannier, E., Callahan, M.V. and Dinarello, C.A. (1992) Effect of Interleukin-1 (IL-1) Blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood, 79, 2356-2363.
[25] Schytte Blix, I.J., Helgeland, K., Hvattum, E. and Lyberg, T. (1999) Lipopolysaccharide from Actinobacillus actionmecetemcomitans stimulates production of intrleukin-1β, tumor necrosis factor-α, interleukin-6 and interleukin-1 receptor antagonist in human whole blood. Journal of Periodontal Research, 34, 34-40. doi:10.1111/j.1600-0765.1999.tb02219.x
[26] Vigers, G.P., Caffes, P., Evans, R.J., Thompson, R.C., Eisenberg, S.P. and Brandhuber, B.J. (1994) X-ray structure of interleukin-1 receptor antagonist at 2.0-A resolution. The Journal of Biological Chemistry, 269, 12874-12879.
[27] Fletcher, J., Reddi, K., Poole, S., Nair, S., Henderson, B., Tabona, P. and Wilson, M. (1997) Interactions between periodontopathogenic bacteria and cytokines. Journal of Periodontal Research, 32, 200-205. doi:10.1111/j.1600-0765.1997.tb01406.x
[28] Kabashima, H., Nagata, K., Hashiguchi, I., Toriya, Y., Iijima, T., Maki, K. and Maeda, K. (1996) Interleukin-1 receptor antagonist and interleukin-4 in gingival crevicular fluid of patients with inflammatory periodontal disease. Journal of Oral Pathology & Medicine, 25, 449-455. doi:10.1111/j.1600-0714.1996.tb00295.x
[29] Holmlund, A., Hanstrom, L. and Lerner, U.H. (2004) Bone resorbing activity and cytokine levels in gingival crevicular fluid before and after treatment of periodontal disease. Journal of Periodontology, 31, 475-482. doi:10.1111/j.1600-051X.2004.00504.x
[30] Nishihara, T., Ohsaki, Y., Ueda, N., Saito, N. and Mundy, G.R. (1994) Mouse Interleukin-1 receptor antagonist induced by Actinobacillus actinomycetemcomitans lipopolysaccharide blocks the effects of interleukin-1 on bone resorption and osteoclast like cell formation. Infection and Immunity, 62, 390-397.
[31] Oates, T.W., Graves, D.T. and Cochran, D.L. (2002) Clinical, radiographic and biochemical assessment of IL-1/ TNF-α antagonist inhibition of bone loss in experimental periodontitis. Journal of Periodontology, 29, 137-143. doi:10.1034/j.1600-051x.2002.290208.x
[32] Rasmussen, L., Hanstrom, L. and Lerner, U.H. (2000) Characterization of bone resorbing activity in gingival crevicular fluid from patient with periodontitis. Journal of Periodontology, 27, 41-52. doi:10.1034/j.1600-051x.2000.027001041.x
[33] Delima, A.J., Oates, T., Assuma, R., Schwartz, Z., Cochran, D., Amar, S. and Graves, D.T. (2001) Soluble antagonists to interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. Journal of Periodontology, 28, 233-240. doi:10.1034/j.1600-051x.2001.028003233.x
[34] Rawlinson, A., Grummitt, J.M., Walsh, T.F. and Ian Douglas, C.W. (2003) Interleukin 1 and receptor antagonist levels in gingival crevicular fluid in heavy smokers versus non-smokers. Journal of Periodontology, 30, 42-48. doi:10.1034/j.1600-051X.2003.300107.x
[35] Waschul, B., Herforth, A., Stiller-Winkler, R., Idel, H., Granrath, N. and Deinzer, R. (2003) Effect of plaque, psychological stress and gender on crevicular IL-1β and IL-1 ra secretion. Journal of Periodontology, 30, 238-248. doi:10.1034/j.1600-051X.2003.00270.x
[36] Yoshinari, N., Kawase, H., Mitani, A., Ito, M., Sugiishi, S., Matsuoka, M., Shirozu, N., Ishihara, Y., Bito, B., Hiraga, M., Arakawa, K. and Noguchi, T. (2004) Effects of scaling and root planing on the amounts of interleukin-1 and interleukin-1 receptor antagonist and the mRNA expression of interleukin-1β in gingival crevicular fluid and gingival tissues. Journal of Periodontal Research, 39, 158-167. doi:10.1111/j.1600-0765.2004.00722.x
[37] Tarner, I.H. and Fathman, C.G. (2001) Gene therapy in autoimmune disease. Current Opinion in Immunology, 13, 676-682. doi:10.1016/S0952-7915(01)00278-3
[38] Cohen, S.B., Moreland, L.W., Cush, J.J., Greenwald, M.W., Block, S., Shergy, W.J., Hanrahan, P.S., Kraishi, M.M., Patel, A., Sun, G. and Bear, M.B. (2004) A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotreksate. Annals of the Rheumatic Diseases, 63, 1062-1068. doi:10.1136/ard.2003.016014
[39] Clark, W., Jobanputra, P., Barton, P. and Burls, A. (2004) The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adult: A systematic review and economic analysis. Health Technology Assessment, 8, 1-105. doi:10.1016/S0962-8924(00)89088-1
[40] Dinarello, C.A. (1997) Induction of interleukin-1 and interleukin-1 receptor antagonist. Seminars in Oncology, 24, 81-93.
[41] Tracey, K.J. and Cerami, A. (1993) Tumor necrosis factor, other cytokines and diseases. Annual Review of Cell and Developmental Biology, 9, 317-343. doi:10.1146/annurev.cb.09.110193.001533
[42] Vandenabeele, P., Declercq, W., Beyaert, R. and Fiers, W. (1995) Two tumor necrosis factor receptors: Structure and function. Trends in Cell Biology, 5, 392-399.
[43] Beyaert, R. and Fiers, W. (1998) Tumor Necrosis Factor and lymphotoxin. In: Mire-Sluis, A.R. and Thorpe, R., Cytokines (Handbook of Immunopharmacology), Academic Press, San Diego, 335-360.
[44] Schleiffenbaum, B. and Fehr, J. (1990) The tumor necrosis factor receptor and human neutrophil function. Journal of Clinical Investigation, 86, 184-195. doi:10.1172/JCI114683
[45] Aggarwal, B.B., Samanta, A. and Feldmann, M. (2000) TNF receptors. In: Oppenheim, M., Ed., Cytokine Reference, Academic Press, London, 1620-1632.
[46] Della Bianca, V., Dusi, S., Nadalini, K.,A., Donini, M. and Rossi, F. (1995) Role of 55and 75-kD TNF receptors in the potentiation of Fc-mediated phagocytosis in human neutrophils. Biochemical and Biophysical Research Communications, 214, 44-50. doi:10.1006/bbrc.1995.2254
[47] Leboeuf, R.C. and Schreyer, S.A. (1998) The role of tumor necrosis factor α receptors in atherosclerosis. Trends in Cardiovascular Medicine, 8, 131-138. doi:10.1016/S1050-1738(97)00142-4
[48] Ulich, T.R., Yi, E.S., Yin, S., Smith, C. and Remick, D. (1994) Intratracheal administration of endotoxin and cytokines VII. The soluble interleukin-1 receptor and the soluble tumor necrosis factor receptor II (p80) inhibit acute inflammation. Clinical Immunology and Immunopathology, 72, 137-140. doi:10.1006/clin.1994.1117
[49] Howells, G.L. (1995) Cytokine network in destructive periodontal disease. Oral Diseases, 1, 266-270. doi:10.1111/j.1601-0825.1995.tb00192.x
[50] Carteron, N.L. (2000) Cytokines in rheumatoid arthritis: Trial and tribulations. Molecular Medicine Today, 6, 315-323. doi:10.1016/S1357-4310(00)01757-3
[51] Matsuki, Y., Yamamoto, T. and Hara, K. (1992) Detection of inflammatory cytokine messenger RNA (mRNA)— Expressing cells in human inflamed gingiva by combined in situ hybridization and immunohistochemistry. Immunology, 76, 42-47.
[52] Stashenko, P., Jandinski, J.J., Fujiyoshi, P., Rynar, J. and Socransky, S.S. (1991) Tissue levels of bone resorptive cytokines in periodontal disease. Journal of Periodontology, 62, 504-509. doi:10.1902/jop.1991.62.8.504
[53] Beck, J., Garcia, R., Heiss, G, Vokonas, P.S. and Offenbacher, S. (1996) Periodontal disease and cardiovascular disease. Journal of Periodontology, 67, 1123-1137. doi:10.1902/jop.1996.67.10.1123
[54] Lilic, D., Cant, A.J., Abinum, M., Calvert, J.E. and Spickett, G.P. (1996) Chronic mucocutaneous candidiasis: Altered antigen stimulated IL-2, IL-4, IL-6 and interferon-gamma production. Clinical & Experimental Immunology, 105, 205-212. doi:10.1046/j.1365-2249.1996.d01-764.x
[55] Lantz, M., Bjornberg, F., Olsson, I. and Richter, J. (1994) Adherence of neutrophils induces release of soluble tumor necrosis factor receptor forms. The Journal of Immunology, 152, 1362-1369.
[56] McFarlane, C.G., Reynolds, J.J. and Meikle, M.C. (1990) The release of interleukin-1β, tumor necrosis factor-α and interferon-γ by cultured peripheral blood mononuclear cells from patients with periodontitis. Journal of Periodontal Research, 25, 207-214. doi:10.1111/j.1600-0765.1990.tb00906.x
[57] Tervahartiala, T., Koski, H., Xu, J.W., Hayrinen-Immonen, R., Hietanen, J., Sorsa, T. and Konttinen, Y.T. (2001) Tumor necrosis factor-α and its receptors, p-55 and p75 in gingival of adult periodontitis. Journal of Dental Research, 80, 1535-1539. doi:10.1177/00220345010800061101
[58] Graves, D.T., Delima, A.J., Assuma, R., Amar, S., Oates, T. and Cochran, D. (1998) Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. Journal of Periodontology, 69, 1419-1425. doi:10.1902/jop.1998.69.12.1419
[59] Cope, A.P., Aderka, D., Doherty, M., Engelmann, H., Gibbons, D., Jones, A.C., Brennan, F.M., Maini, R.N., Wallach, D. and Feldmann, M. (1992) Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis & Rheumatism, 35, 1160-1169. doi:10.1002/art.1780351008
[60] Sasaki, C.Y. and Patek, P.Q. (1999) Transformation is associated with an increase sensitivity to TNF-mediated lyses as a result of an increase in TNF-induced protein tyrosine phosphatase activity. International Journal of Cancer, 81, 141-147. doi:10.1002/(SICI)1097-0215(19990331)81:1<141::AID-IJC23>3.0.CO;2-V
[61] Hieber, U. and Heim, M.E. (1994) Tumor necrosis factor for the treatment of malignancies. Oncology, 51, 142-153. doi:10.1159/000227329
[62] Bristow, M.R. (1998) Tumor necrosis factor-α and cardiomyopathy. Circulation, 97, 1340-1341. doi:10.1161/01.CIR.97.14.1340
[63] Haak-Frendscho, M., Marsters, S.A., Mordenti, J., Brady, S., Gillett, N.A., Chen, S.A. and Ashkenazi, A. (1994) Inhibition of TNF by a TNF receptor immunoadhesin. Comparison to an anti-TNF monoclonal antibody. The Journal of Immunology, 152, 1347-1353.
[64] Breedveld, F. (1998) New tumor necrosis factor-alpha biologic therapies for rheumatoid arthritis. European Cytokine Network, 9, 233-238.
[65] Feldman, M. and Maini, R.N. (2001) Anti-TNFα therapy of rheumatoid arthritis: What have we learned? Annual Review of Immunology, 19, 163-169. doi:10.1146/annurev.immunol.19.1.163

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