The cytokine network involved in the host immune response to periodontitis

Abstract

Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial community initiates local inflammation, over-activation of the host immune response directly activates osteoclastic activity and alveolar bone loss. Many studies have reported on the cytokine network involved in periodontitis and its crucial and pleiotropic effect on the recruitment of specific immunocytes, control of pathobionts and induction or suppression of osteoclastic activity. Nonetheless, particularities in the stimulation of pathogens in the oral cavity that lead to the specific and complex periodontal cytokine network are far from clarified. Thus, in this review, we begin with an up-to-date aetiological hypothesis of periodontal disease and summarize the roles of cytokines in the host immune response. In addition, we also summarize the latest cytokine-related therapeutic measures for periodontal disease.

References

[1] Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol., 2015, 15: 30-44.

[2] Feng, X. Oral health of Chinese residents: report of the fourth China oral health epidemiological investigation. in Compilation of the 18th Annual Academic Conference of Oral Preventive Medicine (Chinese Stomatological Association, 2018).

[3] Hajishengallis G, Korostoff JM. Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000, 2017, 75: 116-151.

[4] Eke PI, . Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J. Periodontol., 2015, 86: 611-622.

[5] Genco RJ, Van Dyke TE. Prevention: reducing the risk of CVD in patients with periodontitis. Nat. Rev. Cardiol., 2010, 7: 479-480.

[6] Kebschull AM, Demmer RT, Papapanou PN. “Gum bug, leave my heart alone!”—epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis. J. Dent. Res., 2010, 89: 879-902.

[7] Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat. Rev. Endocrinol., 2011, 7: 738-748.

[8] Lundberg K, Wegner N, Yucel-Lindberg T, Venables PJ. Periodontitis in RA—the citrullinated enolase connection. Nat. Rev. Rheumatol., 2010, 6: 727-730.

[9] Madianos PN, Bobetsis YA, Offenbacher S. Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. J. Periodontol., 2013, 40: S170-S180.

[10] Loesche WJ. The specific plaque hypothesis and the antimicrobial treatment of periodontal disease. Dent. Update, 1992, 19: 70-72.

[11] Holt SC, Ebersole J, Felton J, Brunsvold M, Kornman KS. Implantation of Bacteroides gingivalis in nonhuman primates initiates progression of periodontitis. Science, 1988, 239: 55-57.

[12] Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL. Microbial complexes in subgingival plaque. J. Clin. Periodontol., 1998, 25: 134-144.

[13] Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat. Rev. Microbiol., 2010, 8: 481-490.

[14] Orth RH, O’Brien‐Simpson NM, Dashper SG, Reynolds EC. Synergistic virulence of Porphyromonas gingivalis and Treponema denticola in a murine periodontitis model. Mol. Oral. Microbiol, 2011, 26: 229-240.

[15] Settem RP, El-Hassan AT, Honma K, Stafford GP, Sharma A. Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model. Infect. Immun., 2012, 80: 2436-2443.

[16] Hajishengallis G, . Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe, 2011, 10: 497-506.

[17] Jiao Y, . Induction of bone loss by pathobiont-mediated Nod1 signaling in the oral cavity. Cell Host Microbe, 2013, 13: 595-601.

[18] Abusleme L, . The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J., 2013, 7: 1016-1025.

[19] Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol., 2014, 35: 3-11.

[20] Graves D. Cytokines that promote periodontal tissue destruction. J. Periodontol., 2008, 79: 1585-1591.

[21] Boukortt KN, . Association analysis of the IL-1 gene cluster polymorphisms with aggressive and chronic periodontitis in the Algerian population. Arch. Oral. Biol., 2015, 60: 1463-1470.

[22] Ding C, Ji X, Chen X, Xu Y, Zhong L. TNF‐α gene promoter polymorphisms contribute to periodontitis susceptibility: evidence from 46 studies. J. Clin. Periodontol., 2014, 41: 748-759.

[23] Li ZG, Li JJ, Sun CA, Jin Y, Wu WW. Interleukin-18 promoter polymorphisms and plasma levels are associated with increased risk of periodontitis: a meta-analysis. Inflamm. Res., 2014, 63: 45-52.

[24] Tanaka K, . The IL18 promoter polymorphism, rs1946518, is associated with the risk of periodontitis in Japanese women: the Kyushu Okinawa maternal and child health study. Tohoku J. Exp. Med., 2017, 243: 159-164.

[25] Alayan J, . The role of cytokines in a Porphyromonas gingivalis‐induced murine abscess model. Oral. Microbiol. Immunol., 2007, 22: 304-312.

[26] Eskan MA, . The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat. Immunol., 2012, 13: 465-473.

[27] Martuscelli G, Fiorellini JP, Crohin CC, Howell TH. The effect of interleukin‐11 on the progression of ligature‐induced periodontal disease in the beagle dog. J. Periodontol., 2000, 71: 573-578.

[28] Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol., 2018, 39: 276-287.

[29] Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J. Dent. Res., 2019, 98: 148-156.

[30] Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis. Nat. Rev. Microbiol., 2012, 10: 717-725.

[31] Gaffen SL, Hajishengallis G. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res., 2008, 87: 817-828.

[32] Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity, 2019, 50: 778-795.

[33] Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol., 2009, 27: 519-550.

[34] Dinarello CA. Overview of the IL‐1 family in innate inflammation and acquired immunity. Immunol. Rev., 2018, 281: 8-27.

[35] Lavu V, . Polymorphic regions in the interleukin-1 gene and susceptibility to chronic periodontitis: a genetic association study. Genet. Test. Mol. Biomark., 2015, 19: 175-181.

[36] Ben-Sasson SZ, . IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc. Natl Acad. Sci. USA, 2009, 106: 7119-7124.

[37] Langrish CL, . IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med., 2005, 201: 233-240.

[38] Mills KH, Dungan LS, Jones SA, Harris J. The role of inflammasome‐derived IL‐1 in driving IL‐17 responses. J. Leukoc. Biol., 2013, 93: 489-497.

[39] Gilowski L, Wiench R, Płocica I, Krzemiński TF. Amount of interleukin-1β and interleukin-1 receptor antagonist in periodontitis and healthy patients. Arch. Oral. Biol., 2014, 59: 729-734.

[40] Reis C, . Clinical improvement following therapy for periodontitis: association with a decrease in IL1 and IL6. Exp. Ther. Med., 2014, 8: 323-327.

[41] García‐Hernández AL, . Upregulation of proteins of the NLRP3 inflammasome in patients with periodontitis and uncontrolled type 2 diabetes. Oral. Dis., 2019, 25: 596-608.

[42] Isaza‐Guzmán DM, Medina‐Piedrahíta VM, Gutiérrez‐Henao C, Tobón‐Arroyave SI. Salivary levels of NLRP3 inflammasome‐related proteins as potential biomarkers of periodontal clinical status. J. Periodontol., 2017, 88: 1329-1338.

[43] Lapérine O, . Interleukin-33 and RANK-L interplay in the alveolar bone loss associated to periodontitis. PLoS ONE, 2016, 11

[44] Sağlam M, . Levels of interleukin‐37 in gingival crevicular fluid, saliva, or plasma in periodontal disease. J. Periodontal Res., 2015, 50: 614-621.

[45] Buduneli N, Özçaka Ö, Nalbantsoy A. Interleukin‐33 levels in gingival crevicular fluid, saliva, or plasma do not differentiate chronic periodontitis. J. Periodontol., 2012, 83: 362-368.

[46] Kurşunlu SF, Öztürk VÖ, Han B, Atmaca H, Emingil G. Gingival crevicular fluid interleukin-36β (-1F8), interleukin-36γ (-1F9) and interleukin-33 (-1F11) levels in different periodontal disease. Arch. Oral. Biol., 2015, 60: 77-83.

[47] Papathanasiou E, . Gingival crevicular fluid levels of interferon‐γ, but not interleukin‐4 or‐33 or thymic stromal lymphopoietin, are increased in inflamed sites in patients with periodontal disease. J. Periodontal Res., 2014, 49: 55-61.

[48] Tada H, . Porphyromonas gingivalis gingipain-dependently enhances IL-33 production in human gingival epithelial cells. PLoS ONE, 2016, 11

[49] Tada H, . Increases in IL-33 production by fimbriae and lipopeptide from Porphyromonas gingivalis in mouse bone marrow-derived dendritic cells via toll-like receptor 2. Biomed. Res., 2017, 38: 189-195.

[50] Köseoğlu S, Hatipoğlu M, Sağlam M, Enhoş Ş, Esen HH. Interleukin‐33 could play an important role in the pathogenesis of periodontitis. J. Periodontal Res., 2015, 50: 525-534.

[51] Malcolm J, . IL-33 exacerbates periodontal disease through induction of RANKL. J. Dent. Res., 2015, 94: 968-975.

[52] Okamura H, . Cloning of a new cytokine that induces IFN-γ production by T cells. Nature, 1995, 378: 88-91.

[53] Figueredo CM, . Increased interleukin‐18 in gingival crevicular fluid from periodontitis patients. Oral. Microbiol. Immunol., 2008, 23: 173-176.

[54] Özçaka Ö, Nalbantsoy A, Buduneli N. Interleukin‐17 and interleukin‐18 levels in saliva and plasma of patients with chronic periodontitis. J. Periodontal Res., 2011, 46: 592-598.

[55] Sánchez‐Hernández P, . IL‐12 and IL‐18 levels in serum and gingival tissue in aggressive and chronic periodontitis. Oral. Dis., 2011, 17: 522-529.

[56] Campos BO, Fischer RG, Gustafsson A, Figueredo CM. Effectiveness of non-surgical treatment to reduce IL-18 levels in the gingival crevicular fluid of patients with periodontal disease. Braz. Dent. J., 2012, 23: 428-432.

[57] Pradeep AR, Hadge P, Chowdhry S, Patel S, Happy D. Exploring the role of Th1 cytokines: interleukin-17 and interleukin-18 in periodontal health and disease. J. Oral. Sci., 2009, 51: 261-266.

[58] Nair V, Bandyopadhyay P, Kundu D, Das S. Estimation of interleukin-18 in the gingival crevicular fluid and serum of Bengali population with periodontal health and disease. J. Indian Soc. Periodontol., 2016, 20: 260-264.

[59] Hamedi M, . Porphyromonas gingivalis culture supernatants differentially regulate Interleukin-1β and Interleukin-18 in human monocytic cells. Cytokine, 2009, 45: 99-104.

[60] Yee M, Kim A, Alpagot T, Düzgüneş N, Konopka K. Porphyromonas gingivalis stimulates IL-18 secretion in human monocytic THP-1 cells. Microbes Infect., 2012, 14: 684-689.

[61] Wang F, Guan M, Wei L, Yan H. IL18 promotes the secretion of matrix metalloproteinases in human periodontal ligament fibroblasts by activating NFκB signaling. Mol. Med. Rep., 2019, 19: 703-710.

[62] Yoshinaka K, . Increased interleukin-18 in the gingival tissues evokes chronic periodontitis after bacterial infection. Tohoku J. Exp. Med., 2014, 232: 215-222.

[63] Sehgal, P. B., Grieninger, G. & Tosato, G. Regulation of the Acute Phase and Immune Responses (The New York Academy of Sciences, 1989).

[64] Hasegawa H, . Expanding diversity in molecular structures and functions of the IL-6/IL-12 heterodimeric cytokine family. Front. Immunol., 2016, 7: 479.

[65] Jones BE, Maerz MD, Buckner JH. IL-6: a cytokine at the crossroads of autoimmunity. Curr. Opin. Immunol., 2018, 55: 9-14.

[66] Murakami M, Kamimura D, Hirano T. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity, 2019, 50: 812-831.

[67] Collison LW, . The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol., 2012, 13: 290-299.

[68] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity, 2019, 50: 1007-1023.

[69] Riethmueller S, . Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-glycosylation. PLoS Biol., 2017, 15

[70] Kishimoto T, Akira S, Taga T. Interleukin-6 and its receptor: a paradigm for cytokines. Science, 1992, 258: 593-597.

[71] Heinrich PC, . Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J., 2003, 374: 1-20.

[72] Naka T, . Structure and function of a new STAT-induced STAT inhibitor. Nature, 1997, 387: 924-929.

[73] Takahashi-Tezuka M, . Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. Mol. Cell. Biol., 1998, 18: 4109-4117.

[74] Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine, 2014, 70: 11-20.

[75] Lin WW, . The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci. Signal., 2015, 8: ra88.

[76] Jones GW, . Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J. Immunol., 2010, 184: 2130-2139.

[77] Heink S, . Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T_H17 cells. Nat. Immunol., 2017, 18: 74-85.

[78] Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol., 2009, 10: 857-863.

[79] Bettelli E, . Reciprocal developmental pathways for the generation of pathogenic effector T H 17 and regulatory T cells. Nature, 2006, 441: 235-238.

[80] Zhu J, . Interleukin-6-174G/C polymorphism contributes to periodontitis susceptibility: an updated meta-analysis of 21 case-control studies. Dis. Markers, 2016, 2016: 9612421.

[81] Stadler AF, . Gingival crevicular fluid levels of cytokines/chemokines in chronic periodontitis: a meta‐analysis. J. Clin. Periodontol., 2016, 43: 727-745.

[82] Ebersole JL, . Cytokine gene expression profiles during initiation, progression and resolution of periodontitis. J. Clin. Periodontol., 2014, 41: 853-861.

[83] De Benedetti F, . Impaired skeletal development in interleukin‐6–transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum., 2006, 54: 3551-3563.

[84] Wu Q, Zhou X, Huang D, Yingchen J, Kang F. IL-6 enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro. Cell. Physiol. Biochem., 2017, 41: 1360-1369.

[85] Pan W, . Traumatic occlusion aggravates bone loss during periodontitis and activates Hippo‐YAP pathway. J. Clin. Periodontol., 2019, 46: 438-447.

[86] Pan W, . Inhibition of Ctsk alleviates periodontitis and comorbid rheumatoid arthritis via downregulation of the TLR9 signalling pathway. J. Clin. Periodontol., 2019, 46: 286-296.

[87] Santos‐Lima EKN, . Production of interferon gamma, interleukin 6 and interleukin 1β by human peripheral blood mononuclear cells stimulated with novel Lys‐gingipain synthetic peptides. J. Periodontol., 2019, 1: 1-12.

[88] Zhou LN, . Macrophage polarization in human gingival tissue in response to periodontal disease. Oral. Dis., 2019, 25: 265-273.

[89] Zekeridou A, Mombelli A, Cancela J, Courvoisier D, Giannopoulou C. Systemic inflammatory burden and local inflammation in periodontitis: what is the link between inflammatory biomarkers in serum and gingival crevicular fluid?. Clin. Exp. Dent. Res, 2019, 24: 128-135.

[90] Carswell EA, . An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA, 1975, 72: 3666-3670.

[91] Aggarwal BB, Henzel WJ, Moffat B, Kohr WJ, Harkins RN. Primary structure of human lymphotoxin derived from 1788 lymphoblastoid cell line. J. Biol. Chem., 1985, 260: 2334-2344.

[92] Aggarwal BB, . Human tumor necrosis factor. Production, purification, and characterization. J. Biol. Chem., 1985, 260: 2345-2354.

[93] Aggarwal BB, Moffat B, Harkins RN. Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. J. Biol. Chem., 1984, 259: 686-691.

[94] Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol., 2015, 15: 362-374.

[95] Kriegler M, Perez C, DeFay K, Albert I, Lu S. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell, 1988, 53: 45-53.

[96] Black RA, . A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature, 1997, 385: 729-733.

[97] Eck MJ, Sprang SR. The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. J. Biol. Chem., 1989, 264: 17595-17605.

[98] Jones EY, Stuart DI, Walker NPC. Structure of tumour necrosis factor. Nature, 1989, 338: 225-228.

[99] Faustman D, Davis M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov., 2010, 9: 482-493.

[100] Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell, 1995, 81: 495-504.

[101] Hsu H, Huang J, Shu H-B, Baichwal V, Goeddel DV. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity, 1996, 4: 387-396.

[102] Ea C-K, Deng L, Xia Z-P, Pineda G, Chen ZJ. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell, 2006, 22: 245-257.

[103] Li H, Kobayashi M, Blonska M, You Y, Lin X. Ubiquitination of RIP is required for tumor necrosis factor α-induced NF-κB activation. J. Biol. Chem., 2006, 281: 13636-13643.

[104] Tseng W-Y, . TNFR signalling and its clinical implications. Cytokine, 2018, 101: 19-25.

[105] Haas TL, . Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell, 2009, 36: 831-844.

[106] Israël A. The IKK complex, a central regulator of NF-κB activation. Cold Spring Harb. Perspect. Biol., 2010, 2: a000158.

[107] Hoffmann A, Baltimore D. Circuitry of nuclear factor κB signaling. Immunol. Rev., 2006, 210: 171-186.

[108] Wang C, . TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 2001, 412: 346-351.

[109] Kanayama A, . TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell, 2004, 15: 535-548.

[110] Shim J-H, . TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev., 2005, 19: 2668-2681.

[111] Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell, 2003, 114: 181-190.

[112] Wang L, Du F, Wang X. TNF-α induces two distinct caspase-8 activation pathways. Cell, 2008, 133: 693-703.

[113] Hajishengallis G, Shakhatreh M-AK, Wang M, Liang S. Complement receptor 3 blockade promotes IL-12-mediated clearance of Porphyromonas gingivalis and negates its virulence in vivo. J. Immunol., 2007, 179: 2359-2367.

[114] Sun L, . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell, 2012, 148: 213-227.

[115] Murphy JM, . The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity, 2013, 39: 443-453.

[116] Kobayashi K, . Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL–RANK interaction. J. Exp. Med., 2000, 191: 275-286.

[117] Teitelbaum SL. Osteoclasts: culprits in inflammatory osteolysis. Arthritis Res. Ther., 2005, 8: 201.

[118] Kitaura H, . Immunological reaction in TNF-α-mediated osteoclast formation and bone resorption in vitro and in vivo. Clin. Dev. Immunol., 2013, 2013: 181849.

[119] Walsh MC, Choi Y. Biology of the RANKL–RANK–OPG system in immunity, bone, and beyond. Front. Immunol., 2014, 5: 511.

[120] Osta B, Benedetti G, Miossec P. Classical and paradoxical effects of TNF-α on bone homeostasis. Front. Immunol., 2014, 5: 48.

[121] Algate K, Haynes D, Bartold P, Crotti T, Cantley M. The effects of tumour necrosis factor‐α on bone cells involved in periodontal alveolar bone loss; osteoclasts, osteoblasts and osteocytes. J. Periodontal Res., 2016, 51: 549-566.

[122] Madureira DF, . Tumor necrosis factor-alpha in gingival crevicular fluid as a diagnostic marker for periodontal diseases: a systematic review. J. Evid. Based Dent. Pract., 2018, 18: 315-331.

[123] Górska R, . Relationship between clinical parameters and cytokine profiles in inflamed gingival tissue and serum samples from patients with chronic periodontitis. J. Clin. Periodontol., 2003, 30: 1046-1052.

[124] Fujihara R, . Tumor necrosis factor‐α enhances RANKL expression in gingival epithelial cells via protein kinase A signaling. J. Periodontal Res., 2014, 49: 508-517.

[125] Kawai T, . B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am. J. Pathol., 2006, 169: 987-998.

[126] Basso FG, . Tumor necrosis factor‐α and interleukin (IL)‐1β, IL‐6, and IL‐8 impair in vitro migration and induce apoptosis of gingival fibroblasts and epithelial cells, delaying wound healing. J. Periodontol., 2016, 87: 990-996.

[127] Arancibia R, . Tumor necrosis factor‐α inhibits transforming growth factor‐β–stimulated myofibroblastic differentiation and extracellular matrix production in human gingival fibroblasts. J. Periodontol., 2013, 84: 683-693.

[128] Polak D, Shapira L. An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes. J. Clin. Periodontol., 2018, 45: 150-166.

[129] Ceccarelli F, . Periodontitis and rheumatoid arthritis: the same inflammatory mediators?. Mediat. Inflamm., 2019, 2019: 6034546.

[130] Wojno EDT, Hunter CA, Stumhofer JS. The immunobiology of the interleukin-12 family: room for discovery. Immunity, 2019, 50: 851-870.

[131] Oppmann B, . Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 2000, 13: 715-725.

[132] Bazan JF. Emerging families of cytokines and receptors. Curr. Biol., 1993, 3: 603-606.

[133] Floss DM, . Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. Mol. Biol. Cell, 2016, 27: 2301-2316.

[134] Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol., 2003, 3: 133-146.

[135] Glimcher LH. Trawling for treasure: tales of T-bet. Nat. Immunol., 2007, 8: 448-450.

[136] Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity, 2003, 19: 641-644.

[137] Fokkema SJ, . Increased release of IL‐12p70 by monocytes after periodontal therapy. J. Clin. Periodontol., 2003, 30: 1091-1096.

[138] Sharma A, Khattak B, Naagtilak S, Singh G, Bano T. Effect of periodontal therapy on salivary interleukin-12 levels in chronic periodontitis. J. Clin. Diagn. Res., 2014, 8: ZC90-ZC92.

[139] Johnson R, Serio F. Interleukin‐18 concentrations and the pathogenesis of periodontal disease. J. Periodontol., 2005, 76: 785-790.

[140] Gowen M, Mundy GR. Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone resorption in vitro. J. Immunol., 1986, 136: 2478-2482.

[141] Horwood NJ, Elliott J, Martin TJ, Gillespie MT. IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro. J. Immunol., 2001, 166: 4915-4921.

[142] Sasaki H, . Gamma interferon (IFN-γ) and IFN-γ-inducing cytokines interleukin-12 (IL-12) and IL-18 do not augment infection-stimulated bone resorption in vivo. Clin. Diagn. Lab. Immunol., 2004, 11: 106-110.

[143] Leonard WJ, Lin J-X, O’Shea JJ. The γc family of cytokines: basic biology to therapeutic ramifications. Immunity, 2019, 50: 832-850.

[144] Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl Acad. Sci. USA, 1990, 87: 6934-6938.

[145] Lorenzen I, Dingley AJ, Jacques Y, Grötzinger J. The structure of the interleukin-15α receptor and its implications for ligand binding. J. Biol. Chem., 2006, 281: 6642-6647.

[146] Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC. The structure of interleukin-2 complexed with its alpha receptor. Science, 2005, 308: 1477-1480.

[147] Le Gros G, Ben-Sasson SZ, Seder R, Finkelman F, Paul W. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med., 1990, 172: 921-929.

[148] Vitetta ES, . Serological, biochemical, and functional identity of B cell-stimulatory factor 1 and B cell differentiation factor for IgG1. J. Exp. Med., 1985, 162: 1726-1731.

[149] Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000, 2014, 64: 57-80.

[150] Garlet GP. Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. J. Dent. Res., 2010, 89: 1349-1363.

[151] Gemmell E, Yamazaki K, Seymour GJ. Destructive periodontitis lesions are determined by the nature of the lymphocytic response. Crit. Rev. Oral. Biol. Med., 2002, 13: 17-34.

[152] Yao Z, . Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity, 1995, 3: 811-821.

[153] Yao Z, . Human IL-17: a novel cytokine derived from T cells. J. Immunol., 1995, 155: 5483-5486.

[154] Kostulas N, Pelidou SH, Kivisäkk P, Kostulas V, Link H. Increased IL-1β, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke, 1999, 30: 2174-2179.

[155] Kotake S, . IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest., 1999, 103: 1345-1352.

[156] Harrington LE, . Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol., 2005, 6: 1123-1132.

[157] Parham C, . A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol., 2002, 168: 5699-5708.

[158] Lee Y, . Induction and molecular signature of pathogenic T_H17 cells. Nat. Immunol., 2012, 13: 991-999.

[159] McGeachy MJ, . TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T_H-17 cell–mediated pathology. Nat. Immunol., 2007, 8: 1390-1397.

[160] Moutsopoulos NM, . Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. J. Autoimmun., 2012, 39: 294-303.

[161] Zhu L, . Up-regulation of IL-23 p19 expression in human periodontal ligament fibroblasts by IL-1β via concurrent activation of the NF-κB and MAPKs/AP-1 pathways. Cytokine, 2012, 60: 171-178.

[162] Himani GS, Prabhuji MLV, Karthikeyan BV. Gingival crevicular fluid and interleukin‐23 concentration in systemically healthy subjects: their relationship in periodontal health and disease. J. Periodontal Res., 2014, 49: 237-245.

[163] McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity, 2019, 50: 892-906.

[164] Fort MM, . IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity, 2001, 15: 985-995.

[165] Beale J, . Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci. Transl. Med., 2014, 6: 256ra134.

[166] Kohanski MA, . Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol., 2018, 142: 460-469. e467.

[167] Novatchkova M, Leibbrandt A, Werzowa J, Neubüser A, Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem. Sci., 2003, 28: 226-229.

[168] Liu C, . Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal., 2009, 2: ra63.

[169] Qian Y, . The adaptor Act1 is required for interleukin 17–dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol., 2007, 8: 247-256.

[170] Karlsen JR, Borregaard N, Cowland JB. Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-α is controlled by IκB-ζ but neither by C/EBP-β nor C/EBP-δ. J. Biol. Chem., 2010, 285: 14088-14100.

[171] Toy D, . Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol., 2006, 177: 36-39.

[172] Song X, He X, Li X, Qian Y. The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell. Mol. Immunol., 2016, 13: 418-431.

[173] Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol., 2014, 14: 585-600.

[174] Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity, 2015, 43: 1040-1051.

[175] Abusleme L, Moutsopoulos NM. IL‐17: overview and role in oral immunity and microbiome. Oral. Dis., 2017, 23: 854-865.

[176] Conti HR, . IL-17 receptor signaling in oral epithelial cells is critical for protection against oropharyngeal candidiasis. Cell Host Microbe, 2016, 20: 606-617.

[177] Puel A, . Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science, 2011, 332: 65-68.

[178] Zenobia C, Hajishengallis G. Basic biology and role of interleukin‐17 in immunity and inflammation. Periodontol 2000, 2015, 69: 142-159.

[179] Okui T, Aoki Y, Ito H, Honda T, Yamazaki K. The presence of IL-17+/FOXP3+ double-positive cells in periodontitis. J. Dent. Res., 2012, 91: 574-579.

[180] Dutzan N, . A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans. Sci. Transl. Med., 2018, 10: eaat0797.

[181] Xiao E, . Diabetes enhances IL-17 expression and alters the oral microbiome to increase its pathogenicity. Cell Host Microbe, 2017, 22: 120-128. e124.

[182] Vestweber D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol., 2015, 15: 692-704.

[183] Hajishengallis G, Chavakis T. DEL-1-regulated immune plasticity and inflammatory disorders. Trends Mol. Med., 2019, 25: 444-459.

[184] Kourtzelis I, . DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat. Immunol., 2019, 20: 40-49.

[185] Shin J, . DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Sci. Transl. Med., 2015, 7: 307ra155.

[186] Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science, 1976, 193: 1007-1008.

[187] Takeshita T, . Cloning of the gamma chain of the human IL-2 receptor. Science, 1992, 257: 379-382.

[188] Russell SM, . Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science, 1994, 266: 1042-1045.

[189] Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity, 2013, 38: 13-25.

[190] Andrukhov O, . Serum cytokine levels in periodontitis patients in relation to the bacterial load. J. Periodontol., 2011, 82: 885-892.

[191] Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity, 2019, 50: 924-940.

[192] Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu. Rev. Immunol., 2014, 32: 51-82.

[193] Trompouki E, . Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell, 2011, 147: 577-589.

[194] Reddy J, Guenther MG, DeKoter RP, Young RA. Master transcription factors determine cell-type-specific responses to TGF-b signaling. Cell, 2011, 147: 565-576.

[195] Fantini MC, . Cutting edge: TGF-β induces a regulatory phenotype in CD4+ CD25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol., 2004, 172: 5149-5153.

[196] Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol., 2011, 29: 71-109.

[197] Kotenko SV, . Identification and functional characterization of a second chain of the interleukin‐10 receptor complex. EMBO J., 1997, 16: 5894-5903.

[198] Malefyt RDW, Abrams J, Bennett B, Figdor CG, De Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med., 1991, 174: 1209-1220.

[199] Coomes SM, . CD4+ Th2 cells are directly regulated by IL-10 during allergic airway inflammation. Mucosal. Immunol., 2017, 10: 150-161.

[200] Chaudhry A, . Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity, 2011, 34: 566-578.

[201] Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol., 1991, 147: 3815-3822.

[202] Fiorentino DF, . IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol., 1991, 146: 3444-3451.

[203] Murai M, . Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol., 2009, 10: 1178-1184.

[204] Park-Min K-H, . IL-10 suppresses calcium-mediated costimulation of receptor activator NF-κB signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J. Immunol., 2009, 183: 2444-2455.

[205] Cardoso CR, . Characterization of CD4+ CD25+ natural regulatory T cells in the inflammatory infiltrate of human chronic periodontitis. J. Leukoc. Biol., 2008, 84: 311-318.

[206] Dutzan N, Gamonal J, Silva A, Sanz M, Vernal R. Over‐expression of forkhead box P3 and its association with receptor activator of nuclear factor‐κ B ligand, interleukin (IL)‐17, IL‐10 and transforming growth factor‐β during the progression of chronic periodontitis. J. Clin. Periodo., 2009, 36: 396-403.

[207] Kobayashi R, . Induction of IL-10-producing CD4+ T-cells in chronic periodontitis. J. Dent. Res., 2011, 90: 653-658.

[208] Nakajima T, . Regulatory T-cells infiltrate periodontal disease tissues. J. Dent. Res., 2005, 84: 639-643.

[209] Dutzan N, Konkel JE, Greenwell-Wild T, Moutsopoulos NM. Characterization of the human immune cell network at the gingival barrier. Mucosal. Immunol., 2016, 9: 1163-1172.

[210] Wan B, . Recombinant human interleukin-11 (IL-11) is a protective factor in severe sepsis with thrombocytopenia: a case-control study. Cytokine, 2015, 76: 138-143.

[211] Sonis S, . Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters. Cytokine, 1997, 9: 605-612.

[212] Trepicchio WL, . Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J. Clin. Invest., 1999, 104: 1527-1537.

[213] Shaker OG, Ghallab NA. IL-17 and IL-11 G. C. F. levels in aggressive and chronic periodontitis patients: relation to PCR bacterial detection. Mediat. Inflamm., 2012, 2012: 174764.

[214] Ay ZY, . The gingival crevicular fluid levels of interleukin‐11 and interleukin‐17 in patients with aggressive periodontitis. J. Periodontol., 2012, 83: 1425-1431.

[215] Ay ZY, Sütçü R, Uskun E, Bozkurt FY, Berker E. The impact of the IL‐11: IL‐17 ratio on the chronic periodontitis pathogenesis: a preliminary report. Oral. Dis., 2009, 15: 93-99.

[216] Yücel ÖÖ, Berker E, Gariboğlu S, Otlu H. Interleukin‐11, interleukin‐1β, interleukin‐12 and the pathogenesis of inflammatory periodontal diseases. J. Clin. Periodontol., 2008, 35: 365-370.

[217] Devergne O, . A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J. Virol., 1996, 70: 1143-1153.

[218] Pflanz S, . IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4⁺ T cells. Immunity, 2002, 16: 779-790.

[219] Hamano S, . WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity, 2003, 19: 657-667.

[220] McLean MH, . Interleukin-27 is a potential rescue therapy for acute severe colitis through interleukin-10–dependent, T-cell–independent attenuation of colonic mucosal innate immune responses. Inflamm. Bowel Dis., 2017, 23: 1983-1995.

[221] Niedbala W, . Interleukin 27 attenuates collagen-induced arthritis. Ann. Rheum. Dis., 2008, 67: 1474-1479.

[222] Sasaoka T, . Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2010, 300: G568-G576.

[223] Codarri L, . RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol., 2011, 12: 560-567.

[224] Young A, . Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL-27. J. Immunol., 2012, 189: 2079-2083.

[225] Stumhofer JS, . Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol., 2007, 8: 1363-1371.

[226] Fitzgerald DC, . Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27–stimulated T cells. Nat. Immunol., 2007, 8: 1372-1379.

[227] Batten M, . Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol., 2008, 180: 2752-2756.

[228] Mitani A, . Increased expression of interleukin (IL)‐35 and IL‐17, but not IL‐27, in gingival tissues with chronic periodontitis. J. Periodontol., 2015, 86: 301-309.

[229] Babaloo A, Rahbar M, Babaloo Z, Ghasemi S, Amini A. Evaluation of clinical periodontal indices and serum interleukin-27 by one-stage full-mouth disinfection and quadrant scaling and root planing in periodontitis. J. Contemp. Dent. Pr., 2018, 19: 997-1004.

[230] Jia-Jia H, . Comparison of the IL-27 level in gingival crevicular fluid of cross-quadrant and the upper and lower half-mouth subgingival scaling. Shanghai Kou Qiang Yi Xue, 2013, 22: 428-431.

[231] Nold-Petry CA, . IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat. Immunol., 2015, 16: 354-365.

[232] Sarhan D, . Adaptive NK cells resist regulatory T-cell suppression driven by IL37. Cancer Immunol. Res., 2018, 6: 766-775.

[233] Jing L, . IL-37-and IL-35/IL-37-producing plasma cells in chronic periodontitis. J. Dent. Res., 2019, 98: 813-821.

[234] Offenbacher S, . GWAS for interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation. Nat. Commun., 2018, 9

[235] McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat. Rev. Rheumatol., 2016, 12: 63-68.

[236] Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity, 2019, 50: 992-1006.

[237] Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N. Pathogenesis of ankylosing spondylitis—recent advances and future directions. Nat. Rev. Rheumatol., 2017, 13: 359-367.

[238] Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annu. Rev. Immunol., 2014, 32: 227-255.

[239] Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity, 2019, 50: 975-991.

[240] Vivar N, Van Vollenhoven RF. Advances in the treatment of rheumatoid arthritis. F1000 Prime Rep., 2014, 6: 31.

[241] Pers JO, Saraux A, Pierre R, Youinou P. Anti–TNF‐α immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis. J. Periodontol., 2008, 79: 1645-1651.

[242] Mayer Y, Balbir‐Gurman A, Machtei EE. Anti‐tumor necrosis factor‐alpha therapy and periodontal parameters in patients with rheumatoid arthritis. J. Periodontol., 2009, 80: 1414-1420.

[243] Mayer Y, Elimelech R, Balbir‐Gurman A, Braun‐Moscovici Y, Machtei EE. Periodontal condition of patients with autoimmune diseases and the effect of anti‐tumor necrosis factor‐α therapy. J. Periodontol., 2013, 84: 136-142.

[244] Ortiz P, . Periodontal therapy reduces the severity of active rheumatoid arthritis in patients treated with or without tumor necrosis factor inhibitors. J. Periodontol., 2009, 80: 535-540.

[245] Oates T, Graves D, Cochran DL. Clinical, radiographic and biochemical assessment of IL‐1/TNF‐α antagonist inhibition of bone loss in experimental periodontitis. J. Clin. Periodontol., 2002, 29: 137-143.

[246] Di Paola R, . Effects of etanercept, a tumour necrosis factor‐α antagonist, in an experimental model of periodontitis in rats. Br. J. Pharm., 2007, 150: 286-297.

[247] Liu Z, . Nanofibrous spongy microspheres to distinctly release miRNA and growth factors to enrich regulatory T cells and rescue periodontal bone loss. ACS Nano, 2018, 12: 9785-9799.

Funding

National Natural Science Foundation of China (National Science Foundation of China)(81730030, 81621062)