This narrative review systematically synthesizes current preclinical and clinical evidence from PubMed-based electronic database searches to comprehensively elucidate the functional roles of interleukin (IL)-35, IL-37, and IL-38 in the pathogenesis of periodontitis and explore their translational potential for innovative periodontal therapeutic strategies. Existing studies demonstrate that these three cytokines exert crucial immunomodulatory effects on periodontal immune homeostasis with distinct expression patterns and functional characteristics. IL-35 is compensatorily upregulated in the local tissues and biofluids of periodontitis patients in a disease severity-dependent manner, and it protects periodontal tissues by remodeling the Th17/Treg/Breg immune balance, suppressing pro-inflammatory signaling pathways, and inhibiting osteoclastogenesis, while its local anti-inflammatory expression is markedly impaired by smoking and diabetes. IL-37 is elevated in periodontitis gingival lesions but downregulated in specific inflammatory models, serving as a vital anti-inflammatory mediator that blocks the NF-κB/NLRP3 signaling pathways, regulates macrophage polarization, and alleviates alveolar bone resorption and periodontal matrix degradation, with its biological function further modulated by genetic polymorphisms. Research on IL-38 remains in the preliminary stage, and available data indicate that its expression increases with inflammatory progression and is strongly correlated with clinical periodontal indicators, maintaining periodontal immune homeostasis mainly via antagonizing the IL-36 receptor, while inconsistent expression results in relevant studies are largely attributed to methodological heterogeneity. Collectively, IL-35, IL-37, and IL-38 act as key local immunomodulators that construct a complementary anti-inflammatory regulatory network together with IL-10, participating in the modulation of immune cell differentiation, inhibition of inflammatory cascade activation, and suppression of alveolar bone and connective tissue destruction during periodontitis development. Their aberrant expression profiles are closely associated with periodontitis progression, endowing them with great potential as non-invasive biomarkers for disease evaluation and therapeutic monitoring, as well as promising targets for periodontal immunotherapy. Nevertheless, current research still has inherent limitations including incomplete mechanistic exploration and insufficient clinical validation, and further translational studies are urgently needed to promote the clinical application of these cytokines and advance the development of precision periodontology.

Yalin Han, Shan Zhao, Hui Wang, Shengmei Wei, Jia Xu, Yuan Hu, Xinyue Li, Yingying Han. Immunomodulatory Effects of Novel Anti-Inflammatory Interleukins in Periodontitis. Academic Journal of Medicine & Health Sciences (2026), Vol. 7, Issue 3: 27-36. https://doi.org/10.25236/AJMHS.2026.070305.

[1] KWON T, LAMSTER I B, LEVIN L. Current Concepts in the Management of Periodontitis[J]. International Dental Journal, 2021, 71(6): 462-476.

[2] TIBÚRCIO‐MACHADO C S, MICHELON C, ZANATTA F B, et al. The global prevalence of apical periodontitis: a systematic review and meta-analysis[J]. International Endodontic Journal, 2021, 54(5): 712-735.

[3] NASCIMENTO G G, ALVES‐COSTA S, ROMANDINI M. Burden of severe periodontitis and edentulism in 2021, with projections up to 2050: The Global Burden of Disease 2021 study[J]. Journal of Periodontal Research, 2024, 59(5): 823-867.

[4] EKE P I, WEI L, BORGNAKKE W S, et al. Periodontitis prevalence in adults ≥ 65 years of age, in the USA[J]. Periodontology 2000, 2016, 72(1): 76-95.

[5] TRINDADE D, CARVALHO R, MACHADO V, et al. Prevalence of periodontitis in dentate people between 2011 and 2020: A systematic review and meta-analysis of epidemiological studies[J]. Journal of Clinical Periodontology, 2023, 50(5): 604-626.

[6] HAAS A N, FURLANETO F, GAIO E J, et al. New tendencies in non-surgical periodontal therapy[J]. Brazilian Oral Research, 2021, 35(suppl 2): e095.

[7] BALTA M G, PAPATHANASIOU E, BLIX I J, et al. Host Modulation and Treatment of Periodontal Disease[J]. Journal of Dental Research, 2021, 100(8): 798-809.

[8] DANNEWITZ B, HOLTFRETER B, EICKHOLZ P. Periodontitis-therapy of a widespread disease[J]. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz, 2021, 64(8): 931-940.

[9] NEURATH N, KESTING M. Cytokines in gingivitis and periodontitis: from pathogenesis to therapeutic targets[J]. Frontiers in Immunology, 2024, 15: 1435054.

[10] PAPATHANASIOU E, CONTI P, CARINCI F, et al. IL-1 Superfamily Members and Periodontal Diseases[J]. Journal of Dental Research, 2020, 99(13): 1425-1434.

[11] DINARELLO C A. Overview of the IL-1 family in innate inflammation and acquired immunity[J]. Immunological Reviews, 2018, 281(1): 8-27.

[12] SAID-SADIER N, SAYEGH B, FARAH R, et al. Association between Periodontal Disease and Cognitive Impairment in Adults[J]. International Journal of Environmental Research and Public Health, 2023, 20(6): 4707.

[13] PLEMMENOS G, EVANGELIOU E, POLIZOGOPOULOS N, et al. Central Regulatory Role of Cytokines in Periodontitis and Targeting Options[J]. Current Medicinal Chemistry, 2021, 28(15): 3032-3058.

[14] SONG M, MA X. The Immunobiology of Interleukin-35 and Its Regulation and Gene Expression[J]. Advances in Experimental Medicine and Biology, 2016, 941: 213-225.

[15] YE C, YANO H, WORKMAN C J, et al. Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases[J]. Journal of Interferon & Cytokine Research, 2021, 41(11): 391-406.

[16] XIE Y, ZHANG H, HUANG J, et al. Interleukin-35 in autoimmune dermatoses: Current concepts[J]. Open Medicine, 2022, 17(1): 589-600.

[17] ZHANG Y, WEI S, WU Q, et al. Interleukin-35 promotes Breg expansion and interleukin-10 production in CD19+ B cells in patients with ankylosing spondylitis[J]. Clinical Rheumatology, 2022, 41(8): 2403-2416.

[18] WANG L, CHRISTODOULOU M I, JIN Z, et al. Human regulatory B cells suppress autoimmune disease primarily via interleukin-37[J]. Journal of Autoimmunity, 2025, 153: 103415.

[19] YAZDANI R, NAZIRI H, AZIZI G, et al. IL-37 suppresses CNS autoimmunity by increasing the frequency of Treg cells and reducing CD4 + T cell-derived IL-10 production[J]. Journal of Neuroinflammation, 2024, 21(1): 301.

[20] JIA H, LIU J, HAN B. Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases[J]. BioMed Research International, 2018, 2018: 3058640.

[21] ESMAEILZADEH A, BAHMAIE N, NOURI E, et al. Immunobiological Properties and Clinical Applications of Interleukin-38 for Immune-Mediated Disorders: A Systematic Review Study[J]. International Journal of Molecular Sciences, 2021, 22(22): 12552.

[22] DE GRAAF D M, MAAS R J A, SMEEKENS S P, et al. Human recombinant interleukin-38 suppresses inflammation in mouse models of local and systemic disease[J]. Cytokine, 2021, 137: 155334.

[23] HAN M M, YUAN X R, SHI X, et al. The Pathological Mechanism and Potential Application of IL-38 in Autoimmune Diseases[J]. Frontiers in Pharmacology, 2021, 12: 732790.

[24] XIA H S, LIU Y, FU Y, et al. Biology of interleukin-38 and its role in chronic inflammatory diseases[J]. International Immunopharmacology, 2021, 95: 107528.

[25] MITANI A, NIEDBALA W, FUJIMURA T, et al. Increased expression of interleukin (IL)-35 and IL-17, but not IL-27, in gingival tissues with chronic periodontitis[J]. Journal of Periodontology, 2015, 86(2): 301-309.

[26] ALTACA M, CEBESOY E I, KOCAK-OZTUG N A, et al. Interleukin-6, -17, and -35 levels in association with clinical status in stage III and stage IV periodontitis: a cross-sectional study[J]. BMC Oral Health, 2024, 24(1): 1015.

[27] PASHOVA-TASSEVA Z, MLACHKOVA A, KOTSILKOV K, et al. The Multifaceted Role of IL-35 in Periodontal Disease and Beyond: From Genetic Polymorphisms to Biomarker Potential[J]. Genes, 2025, 16(8): 891.

[28] TASKALDIRAN E S, TUTER G, YUCEL A A, et al. Effects of smoking on the salivary and GCF levels of IL-17 and IL-35 in periodontitis[J]. Odontology, 2024, 112(2): 616-623.

[29] SCHMIDLIN P R, DEHGHANNEJAD M, FAKHERAN O. Interleukin-35 pathobiology in periodontal disease: a systematic scoping review[J]. BMC Oral Health, 2021, 21(1): 139.

[30] CAFFERATA E A, TERRAZA‐AGUIRRE C, BARRERA R, et al. Interleukin-35 inhibits alveolar bone resorption by modulating the Th17/Treg imbalance during periodontitis[J]. Journal of Clinical Periodontology, 2020, 47(6): 676-688.

[31] 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[J]. Inflammation, 2019, 42(3): 835-840.

[32] KAMIYA Y, KIKUCHI T, GOTO H, et al. IL-35 and RANKL Synergistically Induce Osteoclastogenesis in RAW264 Mouse Monocytic Cells[J]. International Journal of Molecular Sciences, 2020, 21(6): 2069.

[33] LI S, SU L, LUAN Q, et al. Regulatory B cells induced by interleukin-35 inhibit inflammation and alveolar bone resorption in ligature-induced periodontitis[J]. Journal of Periodontology, 2023, 94(11): 1376-1388.

[34] WANG H, ZHANG H. The Role of IL-12 Family Cytokines in the Pathogenesis of Periodontal Disease: A Therapeutic Approach[J]. Immunological Investigations, 2026, 55(2): 409-447.

[35] JING L, KIM S, SUN L, et al. IL-37- and IL-35/IL-37-Producing Plasma Cells in Chronic Periodontitis[J]. Journal of Dental Research, 2019, 98(7): 813-821.

[36] OFFENBACHER S, JIAO Y, KIM S J, et al. GWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation[J]. Nature Communications, 2018, 9(1): 3686.

[37] TALMAC A C, CALISIR M, EROGLU E G, et al. Effects of Er,Cr:YSGG and Diode Lasers on Clinical Parameters and Gingival Crevicular Fluid IL-1β and IL-37 Levels in Generalized Aggressive Periodontitis[J]. Mediators of Inflammation, 2019, 2019: 2780794.

[38] SAĞLAM M, KÖSEOĞLU S, SAVRAN L, et al. Levels of interleukin-37 in gingival crevicular fluid, saliva, or plasma in periodontal disease[J]. Journal of Periodontal Research, 2015, 50(5): 614-621.

[39] HASSAN Z M, AKRAM H M. Salivary Biomarkers of Inflammasome Activation in Unstable Periodontitis: A Case-Control Study[J]. European Journal of Dentistry, 2026, 20(01): 272-286.

[40] BEKLEN A, YAVUZ M B, UCKAN D. Interleukin-37 reduces lipopolysaccharide induced matrix metalloproteinase-9 in gingival epithelial cells[J]. BMC Oral Health, 2025, 25(1): 637.

[41] YANG L, TAO W, XIE C, et al. Interleukin-37 ameliorates periodontitis development by inhibiting NLRP3 inflammasome activation and modulating M1/M2 macrophage polarization[J]. Journal of Periodontal Research, 2024, 59(1): 128-139.

[42] LI L, LI J, LI S, et al. IL-37 alleviates alveolar bone resorption and inflammatory response through the NF-κB/NLRP3 signaling pathway in male mice with periodontitis[J]. Archives of Oral Biology, 2023, 147: 105629.

[43] SAEED J, KITAURA H, KIMURA K, et al. IL-37 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption in vivo[J]. Immunology Letters, 2016, 175: 8-15.

[44] WU P, ZHOU J, WU Y, et al. The emerging role of Interleukin 37 in bone homeostasis and inflammatory bone diseases[J]. International Immunopharmacology, 2021, 98: 107803.

[45] CLOITRE A, HALGAND B, SOURICE S, et al. IL-36γ is a pivotal inflammatory player in periodontitis-associated bone loss[J]. Scientific Reports, 2019, 9(1): 19257.

[46] H K, M H, NA K. Interleukin-38: A crucial player in periodontitis[J]. Oral diseases, 2023.

[47] TORAMAN A, SAĞLAM E, SAVRAN L, et al. Evaluation of Salivary Il-38 Levels in Periodontitis: A Cross-Sectional Study[J]. Journal of Interferon & Cytokine Research: The Official Journal of the International Society for Interferon and Cytokine Research, 2025, 45(2): 76-82.

[48] WANG Y, ANDERSON E P, TATAKIS D N. Whole transcriptome analysis of smoker palatal mucosa identifies multiple downregulated innate immunity genes[J]. Journal of Periodontology, 2020, 91(6): 756-766.

[49] J L, H M, Y M, et al. IL-36 Regulates Neutrophil Chemotaxis and Bone Loss at the Oral Barrier[J]. Journal of dental research, 2024, 103(4).