IL-1 Receptor Type II Production Is Upregulated by IL-4 and IL-13, and Downregulated by IFN-γ in Mouse Gingival Epithelial Cells


Background and Objective: Interleukin-1 (IL-1) binds to 2 distinct and separate receptors, types I and II (IL-1RI and IL-1RII, respectively). The binding of IL-1 to IL-1RI induces cellular signaling and biological effects, whereas binding to IL-1RII does not induce cellular signaling and indirectly inhibits IL-1 biological activities such as that of the decoy receptor. Recently, Suzukiet al.reported that soluble IL-1RII (sIL-1RII) was detected in gingival crevicular fluid from a periodontitis patient. However, it remains unclear which cells produce sIL-1RII detected in periodontal tissues. We examined the localization of IL-1RII producing cells in gingival tissues as well as related production control mechanisms. Material and Methods: IL-1RII mRNA expression in gingival epithelial cells (GE1) was performed by real-time PCR analysis, while the amount of sIL-1RII production in supernatant from GE1 cells was examined by dot-blot analysis. Involvement of the phosphorylation of STAT6 in the signaling pathway was determined by western blot analysis. Statistical analysis was performed with Student’st-test. Results: Culturing with IL-4 and IL-13 significantly increased IL-1RII mRNA to levels 10.5-and 8.89-fold, respectively, above that of the control (p< 0.01), while addition of interferon-γ (IFN-γ) significantly suppressed IL-1RII mRNA by 0.22-fold as compared to the control (p< 0.05). Soluble IL-1RII in the supernatant of cultured GE1 cells was increased by IL-4 and IL-13, and decreased by IFN-γ, while western blotting determines the suppression of IL-1RII production by IFN-γ. Without the addition of IL-4 or IL-13 with or without IFN-γ, P-Tyr-STAT6 was not detected. Conclusion: IL-1RII mRNA expression and sIL-1RII production were increased by IL-4 and IL-13, and decreased by IFN-γ. Finally, IL-4 signaling was regulated by IFN-γ through phosphorylation of STAT6 and IL-13 signaling blockage by IFN-γ downstream of STAT6 translocation.

Share and Cite:

Kamiya, Y. , Ishihara, Y. , Kamei, H. , Ozawa, Y. , Mizutani, H. , Kubo, K. , Maeda, H. and Noguchi, T. (2014) IL-1 Receptor Type II Production Is Upregulated by IL-4 and IL-13, and Downregulated by IFN-γ in Mouse Gingival Epithelial Cells. Modern Research in Inflammation, 3, 37-47. doi: 10.4236/mri.2014.32005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Zijnge, V., Ammann, T., Thurnheer, T. and Gmur, R. (2012) Subgingival Biofilm Structure. Frontiers of Oral Biology, 15, 1-16.
[2] Teles, R.P., Gursky, L.C., Faveri, M., Rosa, E.A., Teles, F.R., Feres, M., Socransky, S.S. and Haffajee, A.D. (2010) Relationships between Subgingival Microbiota and GCF Biomarkers in Generalized Aggressive Periodontitis. Journal of Clinical Periodontology, 37, 313-323.
[3] Heitz-Mayfield, L.J. (2005) Disease Progression: Identification of High-Risk Groups and Individuals for Periodontitis. Journal of Clinical Periodontology, 32, 196-209.
[4] Kinane, D.F., Peterson, M. and Stathopoulou, P.G. (2006) Environmental and Other Modifying Factors of the Periodontal Diseases. Periodontology 2000, 40, 107-119.
[5] Beck, J.D. (1994) Methods of Assessing Risk for Periodontitis and Developing Multifactorial Models. Journal of Periodontology, 65, 468-478.
[6] Zambon, J.J. (1996) Periodontal Diseases: Microbial Factors. Annals of Periodontology/The American Academy of Periodontology, 1, 879-925.
[7] Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M.T. and Martin, T.J. (1999) Modulation of Osteoclast Differentiation and Function by the New Members of the Tumor Necrosis Factor Receptor and Ligand Families. Endocrine reviews, 20, 345-357.
[8] Sims, J.E., Gayle, M.A., Slack, J.L., Alderson, M.R., Bird, T.A., Giri, J.G., Colotta, F., Re, F., Mantovani, A., Shanebeck, K., et al. (1993) Interleukin 1 Signaling Occurs Exclusively via the Type I Receptor. Proceedings of the National Academy of Sciences of the United States of America, 90, 6155-6159.
[9] Dinarello, C.A. (1998) Interleukin-1, Interleukin-1 Receptors and Interleukin-1 Receptor Antagonist. International Reviews of Immunology, 16, 457-499.
[10] Clark, W., Jobanputra, P., Barton, P. and Burls, A. (2004) The Clinical and Cost-Effectiveness of Anakinra for the Treatment of Rheumatoid Arthritis in Adults: A Systematic Review and Economic Analysis. Health Technology Assessment, 8, iii-iv, ix-x, 1-105.
[11] Kanda-Nakamura, C., Izumi, Y. and Sueda, T. (1996) Increased Expression of Interleukin-1 Receptors on Fibroblasts Derived from Inflamed Gingiva. Journal of Periodontology, 67, 1267-1273.
[12] Chou, H.H., Takashiba, S., Maeda, H., Naruishi, K., Nishimura, F., Arai, H., Lu, H. and Murayama, Y. (2000) Induction of Intracellular Interleukin-1 Beta Signals via Type II Interleukin-1 Receptor in Human Gingival Fibroblasts. Journal of dental research, 79, 1683-1688. 00220345000790090801
[13] Akoum, A., Jolicoeur, C., Kharfi, A. and Aube, M. (2001) Decreased Expression of the Decoy Interleukin-1 Receptor Type II in Human Endometriosis. The American Journal of Pathology, 158, 481-489.
[14] Suzuki, M., Ishihara, Y., Kamiya, Y., Koide, M., Fuma, D., Fujita, S., Matsumura, Y., Suga, T., Kamei, H. and Noguchi, T. (2008) Soluble Interleukin-1 Receptor Type II Levels in Gingival Crevicular Fluid in Aggressive and Chronic Periodontitis. Journal of Periodontology, 79, 495-500.
[15] Konopka, L., Pietrzak, A. and Brzezinska-Blaszczyk, E. (2012) Effect of Scaling and Root Planing on Interleukin-1 Beta, Interleukin-8 and MMP-8 Levels in Gingival Crevicular Fluid from Chronic Periodontitis Patients. Journal of Periodontal Research, 47, 681-688.
[16] Zhao, J.J., Feng, X.P., Zhang, X.L. and Le, K.Y. (2012) Effect of Porphyromonas gingivalis and Lactobacillus acidophilus on Secretion of IL1B, IL6, and IL8 by Gingival Epithelial Cells. Inflammation, 35, 1330-1337.
[17] Hatakeyama, S., Ohara-Nemoto, Y., Yanai, N., Obinata, M., Hayashi, S. and Satoh, M. (2001) Establishment of Gingival Epithelial Cell Lines from Transgenic Mice Harboring Temperature Sensitive Simian Virus 40 Large T-Antigen Gene. Journal of Oral Pathology & Medicine: Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology, 30, 296-304.
[18] Iwata, T., Mitani, A., Ishihara, Y., Tanaka, S., Yamamoto, G., Kikuchi, T., Naganawa, T., Matsumura, Y., Suga, T., Koide, M., Sobue, T., Suzuki, T. and Noguchi, T. (2005) Actinobacillus actinomycetemcomitans Y4 Capsular Polysaccharide Induces IL-1Beta mRNA Expression through the JNK Pathway in Differentiated THP-1 Cells. Clinical and Experimental Immunology, 141, 261-269.
[19] Giri, J.G., Wells, J., Dower, S.K., McCall, C.E., Guzman, R.N., Slack, J., Bird, T.A., Shanebeck, K., Grabstein, K.H., Sims, J.E., et al. (1994) Elevated Levels of Shed Type II IL-1 Receptor in Sepsis. Potential Role for Type II Receptor in Regulation of IL-1 Responses. Journal of Immunology, 153, 5802-5809.
[20] Spriggs, M.K., Lioubin, P.J., Slack, J., Dower, S.K., Jonas, U., Cosman, D., Sims, J.E. and Bauer, J. (1990) Induction of an Interleukin-1 Receptor (IL-1R) on Monocytic Cells. Evidence That the Receptor Is Not Encoded by a T Cell-Type IL-1R mRNA. The Journal of Biological Chemistry, 265, 22499-22505.
[21] Colotta, F., Re, F., Muzio, M., Polentarutti, N., Minty, A., Caput, D., Ferrara, P. and Mantovani, A. (1994) Interleukin-13 Induces Expression and Release of Interleukin-1 Decoy Receptor in Human Polymorphonuclear Cells. The Journal of Biological Chemistry, 269, 12403-12406.
[22] Symons, J.A., Eastgate, J.A. and Duff, G.W. (1991) Purification and Characterization of a Novel Soluble Receptor for Interleukin 1. The Journal of Experimental Medicine, 174, 1251-1254.
[23] Presland, R.B. and Jurevic, R.J. (2002) Making Sense of the Epithelial Barrier: What Molecular Biology and Genetics Tell Us about the Functions of Oral Mucosal and Epidermal Tissues. Journal of Dental Education, 66, 564-574.
[24] Bahri, R., Saidane-Mosbahi, D. and Rouabhia, M. (2010) Candida famata Modulates Toll-Like Receptor, Beta-De-fensin, and Proinflammatory Cytokine Expression by Normal Human Epithelial Cells. Journal of Cellular Physiology, 222, 209-218.
[25] Cubitt, C.L., Lausch, R.N. and Oakes, J.E. (2001) Synthesis of Type II Interleukin-1 Receptors by Human Corneal Epithelial Cells but Not by Keratocytes. Investigative Ophthalmology & Visual Science, 42, 701-704.
[26] Tominaga, K., Habu, M., Sukedai, M., Hirota, Y., Takahashi, T. and Fukuda, J. (2004) IL-1 Beta, IL-1 Receptor Antagonist and Soluble Type II IL-1 Receptor in Synovial Fluid of Patients with Temporomandibular Disorders. Archives of Oral Biology, 49, 493-499.
[27] de Waal Malefyt, R., Figdor, C.G., Huijbens, R., Mohan-Peterson, S., Bennett, B., Culpepper, J., Dang, W., Zurawski, G. and de Vries, J.E. (1993) Effects of IL-13 on Phenotype, Cytokine Production, and Cytotoxic Function of Human Monocytes. Comparison with IL-4 and Modulation by IFN-Gamma or IL-10. Journal of Immunology, 151, 6370-6381.
[28] Zurawski, G. and de Vries, J.E. (1994) Interleukin 13, an Interleukin 4-Like Cytokine That Acts on Monocytes and B Cells, but Not on T Cells. Immunology Today, 15, 19-26.
[29] Garlet, G.P. (2010) Destructive and Protective Roles of Cytokines in Periodontitis: A Re-Appraisal from Host Defense and Tissue Destruction Viewpoints. Journal of Dental Research, 89, 1349-1363.
[30] Agnello, D., Lankford, C.S., Bream, J., Morinobu, A., Gadina, M., O’Shea, J.J. and Frucht, D.M. (2003) Cytokines and Transcription Factors That Regulate T Helper Cell Differentiation: New Players and New Insights. Journal of Clinical Immunology, 23, 147-161.
[31] Jarnicki, A.G. and Fallon, P.G. (2003) T Helper Type-2 Cytokine Responses: Potential Therapeutic Targets. Current Opinion in Pharmacology, 3, 449-455. 00077-8
[32] Appay, V., van Lier, R.A., Sallusto, F. and Roederer, M. (2008) Phenotype and Function of Human T Lymphocyte Subsets: Consensus and Issues. Cytometry. Part A: The Journal of the International Society for Analytical Cytology, 73, 975-983.
[33] Bluestone, J.A., Mackay, C.R., O’Shea, J.J. and Stockinger, B. (2009) The Functional Plasticity of T Cell Subsets. Nature Reviews. Immunology, 9, 811-816.
[34] Pestka, S., Krause, C.D., Sarkar, D., Walter, M.R., Shi, Y. and Fisher, P.B. (2004) Interleukin-10 and Related Cytokines and Receptors. Annual Review of Immunology, 22, 929-979.
[35] Gorska, R., Gregorek, H., Kowalski, J., Laskus-Perendyk, A., Syczewska, M. and Madalinski, K. (2003) Relationship between Clinical Parameters and Cytokine Profiles in Inflamed Gingival Tissue and Serum Samples from Patients with Chronic Periodontitis. Journal of Clinical Periodontology, 30, 1046-1052.
[36] Kabashima, H., Nagata, K., Maeda, K. and Iijima, T. (2001) Presence of IFN-Gamma and IL-4 in Human Periapical Granulation Tissues and Regeneration Tissues. Cytokine, 14, 289-293.
[37] Suarez, L.J., Ocampo, A.M., Duenas, R.E. and Rodriguez, A. (2004) Relative Proportions of T-Cell Subpopulations and Cytokines That Mediate and Regulate the Adaptive Immune Response in Patients with Aggressive Periodontitis. Journal of Periodontology, 75, 1209-1215.
[38] Fenton, M.J., Buras, J.A. and Donnelly, R.P. (1992) IL-4 Reciprocally Regulates IL-1 and IL-1 Receptor Antagonist Expression in Human Monocytes. Journal of Immunology, 149, 1283-1288.
[39] Orino, E., Sone, S., Nii, A. and Ogura, T. (1992) IL-4 Up-Regulates IL-1 Receptor Antagonist Gene Expression and Its Production in Human Blood Monocytes. Journal of Immunology, 149, 925-931.
[40] Vannier, E., Miller, L.C. and Dinarello, C.A. (1992) Coordinated Antiinflammatory Effects of Interleukin 4: Interleukin 4 Suppresses Interleukin 1 Production but Up-Regulates Gene Expression and Synthesis of Interleukin 1 Receptor Antagonist. Proceedings of the National Academy of Sciences of the United States of America, 89, 4076-4080.
[41] Wong, H.L., Costa, G.L., Lotze, M.T. and Wahl, S.M. (1993) Interleukin (IL) 4 Differentially Regulates Monocyte IL-1 Family Gene Expression and Synthesis in Vitro and in Vivo. The Journal of Experimental Medicine, 177, 775-781.
[42] Dickensheets, H.L. and Donnelly, R.P. (1997) IFN-Gamma and IL-10 Inhibit Induction of IL-1 Receptor Type I and Type II Gene Expression by IL-4 and IL-13 in Human Monocytes. Journal of Immunology, 159, 6226-6233.
[43] Murphy, K.M. and Reiner, S.L. (2002) The Lineage Decisions of Helper T Cells. Nature Reviews. Immunology, 2, 933-944.
[44] Schroder, K., Hertzog, P.J., Ravasi, T. and Hume, D.A. (2004) Interferon-Gamma: An Overview of Signals, Mechanisms and Functions. Journal of Leukocyte Biology, 75, 163-189.
[45] Sallusto, F. and Lanzavecchia, A. (2009) Heterogeneity of CD4+ Memory T Cells: Functional Modules for Tailored Immunity. European Journal of Immunology, 39, 2076-2082.
[46] Garlet, G.P., Martins Jr., W., Ferreira, B.R., Milanezi, C.M. and Silva, J.S. (2003) Patterns of Chemokines and Chemokine Receptors Expression in Different Forms of Human Periodontal Disease. Journal of Periodontal Research, 38, 210-217.
[47] Honda, T., Domon, H., Okui, T., Kajita, K., Amanuma, R. and Yamazaki, K. (2006) Balance of Inflammatory Response in Stable Gingivitis and Progressive Periodontitis Lesions. Clinical and Experimental Immunology, 144, 35-40.
[48] Dutzan, N., Vernal, R., Hernandez, M., Dezerega, A., Rivera, O., Silva, N., Aguillon, J.C., Puente, J., Pozo, P. and Gamonal, J. (2009) Levels of Interferon-Gamma and Transcription Factor T-Bet in Progressive Periodontal Lesions in Patients with Chronic Periodontitis. Journal of Periodontology, 80, 290-296.
[49] Garlet, G.P., Martins Jr., W., Fonseca, B.A., Ferreira, B.R. and Silva, J.S. (2004) Matrix Metalloproteinases, Their Physiological Inhibitors and Osteoclast Factors Are Differentially Regulated by the Cytokine Profile in Human Periodontal Disease. Journal of Clinical Periodontology, 31, 671-679.
[50] 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-1Beta in Gingival Crevicular Fluid and Gingival Tissues. Journal of Periodontal Research, 39, 158-167.
[51] Smith, D.E., Hanna, R., Della, F., Moore, H., Chen, H., Farese, A.M., MacVittie, T.J., Virca, G.D. and Sims, J.E. (2003) The Soluble Form of IL-1 Receptor Accessory Protein Enhances the Ability of Soluble Type II IL-1 Receptor to Inhibit IL-1 Action. Immunity, 18, 87-96.
[52] Yago, T., Nanke, Y., Ichikawa, N., Kobashigawa, T., Mogi, M., Kamatani, N. and Kotake, S. (2009) IL-17 Induces Osteoclastogenesis from Human Monocytes Alone in the Absence of Osteoblasts, Which Is Potently Inhibited by Anti-TNF-Alpha Antibody: A Novel Mechanism of Osteoclastogenesis by IL-17. Journal of Cellular Biochemistry, 108, 947-955.
[53] Cardoso, C.R., Garlet, G.P., Moreira Jr., A.P., W.M., Rossi, M.A. and Silva, J.S. (2008) Characterization of CD4+CD25+ Natural Regulatory T Cells in the Inflammatory Infiltrate of Human Chronic Periodontitis. Journal of Leukocyte Biology, 84, 311-318.
[54] Takahashi, K., Azuma, T., Motohira, H., Kinane, D.F. and Kitetsu, S. (2005) The Potential Role of Interleukin-17 in the Immunopathology of Periodontal Disease. Journal of Clinical Periodontology, 32, 369-374.
[55] Jiang, H., Harris, M.B. and Rothman, P. (2000) IL-4/IL-13 Signaling beyond JAK/STAT. The Journal of Allergy and Clinical Immunology, 105, 1063-1070.
[56] Ohmori, Y., Smith Jr., M.F. and Hamilton, T.A. (1996) IL-4-Induced Expression of the IL-1 Receptor Antagonist Gene Is Mediated by STAT6. Journal of Immunology, 157, 2058-2065.
[57] Kohler, I. and Rieber, E.P. (1993) Allergy-Associated I∈ and Fc∈ Receptor II (CD23b) Genes Activated via Binding of an Interleukin-4-Induced Transcription Factor to a Novel Responsive Element. European Journal of Immunology, 23, 3066-3071.
[58] Kotanides, H. and Reich, N.C. (1996) Interleukin-4-Induced STAT6 Recognizes and Activates a Target Site in the Promoter of the Interleukin-4 Receptor Gene. The Journal of Biological Chemistry, 271, 25555-25561.
[59] Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T. and Akira, S. (1996) Essential Role of Stat6 in IL-4 Signalling. Nature, 380, 627-630.
[60] Shimoda, K., van Deursen, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp, R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A., Doherty, P.C., Grosveld, G., Paul, W.E. and Ihle, J.N. (1996) Lack of IL-4-Induced Th2 Response and IgE Class Switching in Mice with Disrupted Stat6 Gene. Nature, 380, 630-633.
[61] Kaplan, M.H., Schindler, U., Smiley, S.T. and Grusby, M.J. (1996) Stat6 Is Required for Mediating Responses to IL-4 and for Development of Th2 Cells. Immunity, 4, 313-319.
[62] Huang, B.B., Bonish, B.K., Chaturvedi, V., Qin, J.Z. and Nickoloff, B.J. (2001) Keratinocyte CDw60 Expression Is Modulated by Both a Th-1 Type Cytokine IFN-Gamma and Th-2 Cytokines IL-4 and IL-13: Relevance to Psoriasis. The Journal of Investigative Dermatology, 116, 305-312.
[63] Baker, P.J., Evans, R.T. and Roopenian, D.C. (1994) Oral Infection with Porphyromonas gingivalis and Induced Alveolar Bone Loss in Immunocompetent and Severe Combined Immunodeficient Mice. Archives of Oral Biology, 39, 1035-1040.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.