{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T20:15:54Z","timestamp":1790453754446,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009687","name":"Wroclaw Medical University","doi-asserted-by":"publisher","award":["SUBD.B160.26.006"],"award-info":[{"award-number":["SUBD.B160.26.006"]}],"id":[{"id":"10.13039\/501100009687","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SUBD.B160.26.006"],"award-info":[{"award-number":["SUBD.B160.26.006"]}],"id":[{"id":"https:\/\/ror.org\/01qpw1b93","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Temporomandibular disorders (TMDs) are the prevalent causes of orofacial pain and dysfunction of the temporomandibular joint (TMJ) and masticatory muscles. Previous studies have revealed that proinflammatory cytokines play a key role in promoting inflammation, pain, and degeneration within the TMJ. In this context, the present systematic review synthesizes current evidence on various cytokines involved in the pathophysiology of TMDs and evaluates their associations with clinical signs and structural TMJ damage. A PRISMA-guided search (PROSPERO: CRD420251163290) was conducted in PubMed\/MEDLINE, Embase, Scopus, and the Cochrane Library to identify human-based, in vivo, and in vitro studies (January 2014 to September 2025) that assessed the roles of proinflammatory cytokines in TMDs. The following data were extracted from the identified studies: cytokine profiles, sampling methods, clinical outcomes, and TMJ structural changes. Study quality and risk of bias were systematically evaluated. A total of 15 studies (clinical, animal, and mechanistic) were included in the review. Tumor necrosis factor-alpha (TNF-\u03b1), interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), and interleukin-17 (IL-17) consistently emerged as the major contributors to synovitis, cartilage degradation, nociceptive sensitization, and bone resorption. Human studies showed that high levels of TNF-\u03b1, IL-1\u03b2, and IL-6 and chemokines such as C-C motif chemokine ligand 2 (CCL2) and regulated on activation, normal T-cell expressed and secreted (RANTES) were associated with TMJ pain, restricted mandibular motion, crepitus, malocclusion, and erosive changes on imaging. An increased ratio of TNF to soluble TNF receptor in synovial fluid correlated with both pain and condylar damage, suggesting that loss of cytokine control contributes to progressive joint destruction. TMDs, particularly inflammatory and degenerative subtypes, are cytokine-driven pathologies rather than purely mechanical disorders. TNF-\u03b1, IL-1\u03b2, and IL-6 are the promising candidate biomarkers of local inflammation and structural joint pathology. Standardized longitudinal studies are required to validate cytokine-based diagnostics and develop anti-cytokine therapeutics.<\/jats:p>","DOI":"10.3390\/ijms27083677","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T07:57:21Z","timestamp":1776758241000},"page":"3677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Proinflammatory Cytokines in Temporomandibular Disorders: A Systematic Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6109-6809","authenticated-orcid":false,"given":"Zuzanna","family":"Grzech-Le\u015bniak","sequence":"first","affiliation":[{"name":"Department of Experimental Dentistry, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-0793","authenticated-orcid":false,"given":"Agnieszka","family":"Matuszewska","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Wroclaw Medical University, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3173-9389","authenticated-orcid":false,"given":"Jakub","family":"Fiegler-Rudol","sequence":"additional","affiliation":[{"name":"Department of Periodontal Diseases and Oral Mucosa Diseases, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1813-2688","authenticated-orcid":false,"given":"Marwan","family":"El Mobadder","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Faculty of Dental Medicine, Lebanese University, Beirut P.O. Box 6573\/14, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-7413","authenticated-orcid":false,"given":"Rafa\u0142","family":"Wiench","sequence":"additional","affiliation":[{"name":"Department of Periodontal Diseases and Oral Mucosa Diseases, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4953-7143","authenticated-orcid":false,"given":"Mieszko","family":"Wi\u0119ckiewicz","sequence":"additional","affiliation":[{"name":"Department of Experimental Dentistry, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4517042","DOI":"10.1155\/2018\/4517042","article-title":"Pain of Temporomandibular Disorders: From Etiology to Management","volume":"2018","author":"Wieckiewicz","year":"2018","journal-title":"Pain Res. Manag."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.jcms.2019.03.001","article-title":"Antigen-induced arthritis of the temporomandibular joint via repeated injections of bovine serum albumin in domestic pigs","volume":"47","author":"Naujokat","year":"2019","journal-title":"J. Cranio-Maxillofac. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zakrzewska, J. (2009). Orofacial Pain, Oxford University Press Inc.. [1st ed.].","DOI":"10.1093\/med\/9780199236695.001.0001"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41368-021-00129-1","article-title":"A comprehensive review on biomarkers associated with painful temporomandibular disorders","volume":"13","author":"Shrivastava","year":"2021","journal-title":"Int. J. Oral Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1080\/08869634.2017.1342890","article-title":"Expression of Interleukin-1 and temporomandibular disorder: Contemporary review of the literature","volume":"36","author":"Sorenson","year":"2018","journal-title":"Cranio"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.17219\/dmp\/192824","article-title":"Assessment of the relationship between sleep bruxism, reported pain and headache, selected health factors, and general health conditions among temporomandibular disorder patients: A preliminary report","volume":"62","author":"Orzeszek","year":"2025","journal-title":"Dent. Med. Probl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"609","DOI":"10.17219\/dmp\/171894","article-title":"Relationship between pain severity, satisfaction with life and the quality of sleep in Polish adults with temporomandibular disorders","volume":"60","author":"Orzeszek","year":"2023","journal-title":"Dent. Med. Probl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1007\/s10067-025-07593-8","article-title":"Salivary and serum biomarkers profile of patients with rheumatoid arthritis and temporomandibular disorders","volume":"44","author":"Dozet","year":"2025","journal-title":"Clin. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/joor.12611","article-title":"Clinical diagnosis of temporomandibular joint arthritis","volume":"45","author":"Alstergren","year":"2018","journal-title":"J. Oral Rehabil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.17219\/dmp\/203808","article-title":"Exploring the link between temporomandibular disorders and infectious diseases: A systematic review of comorbidities and underlying mechanisms","volume":"62","author":"Osiewicz","year":"2025","journal-title":"Dent. Med. Probl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.17219\/dmp\/147514","article-title":"Degenerative changes of the mandibular condyle in relation to the temporomandibular joint space, gender and age: A multicenter CBCT study","volume":"60","author":"Kurt","year":"2023","journal-title":"Dent. Med. Probl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"549","DOI":"10.17219\/dmp\/177008","article-title":"Assessment of sleep quality in patients with orofacial pain and headache complaints: A polysomnographic study","volume":"61","author":"Orzeszek","year":"2024","journal-title":"Dent. Med. Probl."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s10194-025-01985-6","article-title":"Temporomandibular disorders and mental health: Shared etiologies and treatment approaches","volume":"26","author":"Wan","year":"2025","journal-title":"J. Headache Pain"},{"key":"ref_14","first-page":"309","article-title":"Global co-occurrence of bruxism and temporomandibular disorders: A meta-regression analysis","volume":"62","author":"Ginszt","year":"2025","journal-title":"Dent. Med. Probl."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"D\u0105bkowska, I., Sobiech, L., Cz\u0119pi\u0144ska, A., B\u0119ben, A., Tur\u017ca\u0144ska, K., and Gawda, P. (2025). Multimodal Approaches in the Management of Temporomandibular Disorders: A Narrative Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14124326"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s10194-015-0586-5","article-title":"Reported concepts for the treatment modalities and pain management of temporomandibular disorders","volume":"16","author":"Wieckiewicz","year":"2015","journal-title":"J. Headache Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4853","DOI":"10.1007\/s10067-021-05860-y","article-title":"Corticosteroid injections in the temporomandibular joint temporarily alleviate pain and improve function in rheumatoid arthritis","volume":"40","author":"Kroese","year":"2021","journal-title":"Clin. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/eos.12193","article-title":"Deficient cytokine control modulates temporomandibular joint pain in rheumatoid arthritis","volume":"123","author":"Ahmed","year":"2015","journal-title":"Eur. J. Oral Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.4049\/jimmunol.1303188","article-title":"Estradiol Promotes M1-like Macrophage Activation through Cadherin-11 To Aggravate Temporomandibular Joint Inflammation in Rats","volume":"194","author":"Kou","year":"2015","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1002\/ejp.1021","article-title":"Inflammatory \u2018double hit\u2019 model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1\/R2\u2212\/\u2212 mice","volume":"21","author":"McIlwrath","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105693","DOI":"10.1016\/j.archoralbio.2023.105693","article-title":"Inflammatory and degenerative effects of induced osteoarthritis\/rheumatoid arthritis models on temporomandibular joint of rats","volume":"150","author":"Ananias","year":"2023","journal-title":"Arch. Oral Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18673","DOI":"10.1073\/pnas.1413687112","article-title":"ROR\u03b3t-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells","volume":"111","author":"Park","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"398","DOI":"10.11607\/ofph.2718","article-title":"TMJ Pain and Crepitus Occur Early Whereas Dysfunction Develops Over Time in Rheumatoid Arthritis","volume":"34","author":"Kroese","year":"2020","journal-title":"J. Oral Facial Pain Headache"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Andreev, D., Porschitz, P., Weidner, D., Song, R., Weider, M., Schett, G., G\u00f6lz, L., and Bozec, A. (2025). A multidimensional analysis of temporomandibular joint and ankle joint erosion in inflammatory arthritis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1560723"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Georgi, G.M., Bachmann, F., Luther, J., Derer, A., Heimel, P., Tangl, S., Kahl-Nieke, B., LeBlanc, A., Helms, J., and Schett, G. (2025). The effect of Rsk2 on TNF\u03b1-mediated bone loss in the TMJ and craniofacial skeleton. BMC Oral Health, 25.","DOI":"10.1186\/s12903-025-05779-9"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.neuroscience.2018.09.005","article-title":"The P2X7 Receptor, Cathepsin S and Fractalkine in the Trigeminal Subnucleus Caudalis Signal Persistent Hypernociception in Temporomandibular Rat Joints","volume":"391","author":"Bonfante","year":"2018","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"715","DOI":"10.4103\/1119-3077.164343","article-title":"Temporomandibular disorders in patients with rheumatoid arthritis: A clinical study","volume":"19","author":"Kurtoglu","year":"2016","journal-title":"Niger. J. Clin. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3109\/00016357.2014.994561","article-title":"Tumor necrosis factor mediates temporomandibular joint bone tissue resorption in rheumatoid arthritis","volume":"73","author":"Ahmed","year":"2015","journal-title":"Acta Odontol. Scand."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.jdsr.2023.08.006","article-title":"The role of inflammatory markers in Temporomandibular Myalgia: A systematic review","volume":"59","author":"Aliberas","year":"2023","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/joor.13321","article-title":"Cytokines in temporomandibular joint synovial fluid and tissue in relation to inflammation","volume":"49","author":"Ulmner","year":"2022","journal-title":"J. Oral Rehabil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000047889","article-title":"Inflammation and Bony Changes at the Temporomandibular Joint","volume":"169","author":"Kacena","year":"2001","journal-title":"Cells Tissues Organs"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Soares, J.M., Carneiro, B.D., and Pozza, D.H. (2025). The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26135971"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1248\/bpb.b21-00154","article-title":"The Role of TNF-\u03b1 in the Pathogenesis of Temporomandibular Disorders","volume":"44","author":"Wang","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.cyto.2015.11.005","article-title":"Cytokine profile in the synovial fluid of patients with temporomandibular joint disorders: A systematic review","volume":"77","author":"Kellesarian","year":"2016","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1111\/joor.13041","article-title":"Increased chemokine RANTES in synovial fluid and its role in early-stage degenerative temporomandibular joint disease","volume":"47","author":"Feng","year":"2020","journal-title":"J. Oral Rehabil."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T04:31:34Z","timestamp":1777005094000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083677"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083677","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}