Inflammatory cytokines activity in temporomandibular joint disorders: a review of literature


  • Maria Isabela Guimarães Campos State University of Campinas
  • Paulo Sérgio Flores Campos Federal University of Bahia
  • Sergio Roberto Peres Line State University of Campinas



TMJ. Temporomandibular joint disorders. Osteoarthritis. Cytokines. Interleukins


Cytokines are important polypeptides mediators of acute and chronic inflammation. These molecules act as a complex immunological network, in which there are pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-a (TNF-a), and anti-inflammatory mediators like IL-10 and transforming growth factor-b. In spite of some controversial findings, in general high levels of pro-inflammatory cytokines have been correlated with signs and symptoms of temporomandibular disorders (TMD) such as internal derangement and osteoarthritis. These mediators promote degradation of cartilage and bone joint by inducing release of proteinases and other inflammatory molecules. Indeed, pro-inflammatory cytokines have been associated with temporomandibular joint (TMJ) tissue destruction. However, its mechanisms and pathophysiology have not been clearly delineated. In attempt to summarize the role of cytokines in TMD pathophysiology and its potential for medical intervention, the purpose of the current study was to review the literature concerning the analysis of these inflammatory mediators in TMJ fluid and tissues.


Download data is not yet available.


Metrics Loading ...

Author Biographies

Paulo Sérgio Flores Campos, Federal University of Bahia

master's at Odontology from Universidade Federal da Bahia (1996) and ph.d. at Odontology from Universidade de São Paulo (2001). Has experience in Odontology, focusing on Odontology, acting on the following subjects: tomografia computadorizada por raios x, radiografia, radiografia dentária, articulação temporomandibular and ressonância magnética.

Sergio Roberto Peres Line, State University of Campinas

has graduation at Odontologia by Universidade Estadual de Campinas (1985) , Ph.D. at Patologia Experimental e Comparada by Universidade de São Paulo (1989) and Postdoctorate by National Institute Of Health (1991) . Currently is Servidor público ou celetista of Universidade Estadual de Campinas, Membro de corpo editorial of Journal of Applied Oral Science (Impresso), Membro de corpo editorial of Brazilian Journal of Oral Sciences (Impresso) e of Faculdade de Odontologia de Piracicaba-UNICAMP. Has experience in the area of Odontology. Focused, mainly, in the subjects: Laminina, Matriz extracelular, Menbrana Basal, Metaloproteases. 


Jouvenne P, Vannier E, Dinarello CA, Miossec P. Elevated levels of soluble interleukin-1 receptor type II and interleukin- 1 receptor antagonist in patients with chronic arthritis: correlations with markers of inflammation and joint destruction. Arthritis Rheum. 1998; 41: 1083-9.

Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996; 11: 88-95.

Steiner G, Studnicka-Benke A, Witzmann G, Hofler E, Smolen J. Soluble receptors for tumor necrosis factor and interleukin- 2 in serum and synovial fluid of patients with rheumatoid arthritis, reactive arthritis and osteoarthritis. J Rheumatol. 1995; 22: 406-12.

Kaneyama K, Segami N, Nishimura M, Suzuki T, Sato J. Importance of proinflammatory cytokines in synovial fluid from 121 joints with temporomandibular disorders. Br J Oral Maxillofac Surg. 2002; 40: 418-23.

Kaneyama K, Segami N, Sato J, Nishimura M, Yoshimura H. Interleukin-6 family of cytokines as biochemical markers of osseous changes in the temporomandibular joint disorders. Br J Oral Maxillofac Surg. 2004; 42: 246-50.

Kubota E, Imamura H, Kubota T, Shibata T, Murakami K. Interleukin 1 beta and stromelysin (MMP3) activity of synovial fluid as possible markers of osteoarthritis in the temporomandibular joint. J Oral Maxillofac Surg. 1997; 55: 20-28.

Kubota E, Kubota T, Matsumoto J, Shibata T, Murakami KI. Synovial fluid cytokines and proteinases as markers of temporomandibular joint disease. J Oral Maxillofac Surg. 1998; 56: 192-8.

Fu K, Ma X, Zhang Z, Chen W. Tumor necrosis factor in synovial fluid of patients with temporomandibular disorders. J Oral Maxillofac Surg. 995; 53: 424-6.

Ijima Y, Kobayashi M, Kubota E. Role of interleukin-1 in induction of matrix metalloproteinases synthesized by rat temporomandibular joint chondrocytes and disc cells. Eur J Oral Sci. 2001; 109: 50-9.

Malemud CJ, Goldberg VM. Future directions for research and treatment of osteoarthritis. Front Biosci. 1999; 15: 762-71.

Puzas JE, Landeau JM, Tallents R, Albright J, Schwarz EM, Landesberg R. Degradative pathways in tissues of the temporomandibular joint. Use of in vitro and in vivo models to characterize matrix metalloproteinase and cytokine activity. Cells Tissues Organs. 2001; 169: 248-56.

Kishimoto, T. The biology of interleukin-6. Blood. 1989; 74: 1-10.

May LT, Ghrayeb J, Santhanam U, Tatter SB, Sthoeger Z, Helfgott DC et al. Synthesis and secretion of multiple forms of beta 2-interferon/B-cell differentiation factor 2/ hepatocyte-stimulating factor by human fibroblasts and monocytes. J Biol Chem. 1988; 263: 7760-6.

Mantovani L, Mertelsmann R, Henschler R. Regulation of gene expression of macrophage-colony stimulating factor in human fibroblasts by the acute phase response mediators interleukin (IL)-1 beta, tumor necrosis factor-alpha and IL- 6. FEBS Lett. 1998; 429: 426.

Podor TJ, Jirik FR, Loskutoff DJ, Carson DA, Lotz M. Human endothelial cells produce IL-6. Lack of responses to exogenous IL-6. Ann N Y Acad Sci. 1989; 557: 374-85.

Lotz M, Jirik F, Kabouridis P, Tsoukas C, Hirano T, Kishimoto T et al. B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med. 1988; 167: 1253-8.

Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990; 145: 3297-303.

Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Analysis of tumor necrosis factor-alpha, interleukin-6, interleukin- 1beta, soluble tumor necrosis factor receptors I and II, interleukin-6 soluble receptor, interleukin-1 soluble receptor type II, interleukin-1 receptor antagonist, and protein in the synovial fluid of patients with temporomandibular joint disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005; 99: 276-84.

Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992; 10: 411-52.

Meikle MC, Atkinson SJ, Ward RV, Murphy G, Reynolds JJ. Gingival fibroblasts degrade type I collagen films when stimulated with tumor necrosis factor and interleukin 1: evidence that breakdown is mediated by metalloproteinases. J Periodontal Res. 1989; 24: 207-13.

Elias JA, Gustilo K, Baeder W, Freundlich B. Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor. J Immunol. 1987; 138: 3812-16.

Chaudhary LR, Spelsberg TC, Riggs BL. Production of various cytokines by normal human osteoblast-like cells in response to interleukin-1 beta and tumor necrosis factor-alpha: lack of regulation by 17 beta-estradiol. Endocrinology. 1992; 130: 2528-34.

Bertolini DR, Nedwin GE, Bringman TS, et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986; 319: 516-18.

Van Der Pluijm G, Most W, Van Der Wee-Pals L, de Groot H, Papapoulos S, Lowik C. Two distinct effects of recombinant human tumor necrosis factor-alpha on osteoclast development and subsequent resorption of mineralized matrix. Endocrinology. 1991; 129: 1596-604.

Feldman M. TNF-a: a pivotal role in rheumatoid arthritis. Br J Rheumatol. 1992; 6: 485-516.

Zinman B, Hanley AJG, Harris SB. Circulating tumor necrosis factor-a concentrations in a native canadian population with high rates of type 2 diabetes mellitus. J Clin Endocrinol Metab. 1999; 84: 272-78.

Dinarello CA. Biologic basis for Interleukin-1 in disease. Blood. 1996; 87: 2095-147.

Tatakis DN. Interleukin-1 and bone metabolism: a review. J Periodontol. 1993; 64: 416-31.

Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Levels of soluble cytokine factors in temporomandibular joint effusions seen on magnetic resonance images. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005; 99: 411-8.

Tominaga K, Habu M, Sukedai M, Hirota Y, Takahashi T, Fukuda J. IL-1 beta, IL-1 receptor antagonist and soluble type II IL-1 receptor in synovial fluid of patients with temporomandibular disorders. Arch Oral Biol. 2004; 49: 493-9.

Segami N, Miyamaru M, Nishimura M, Suzuki T, Kaneyama K, Murakami K. Does joint effusion on T2 magnetic resonance images reflect synovitis? Part 2. Comparison of concentration levels of proinflammatory cytokines and total protein in synovial fluid of the temporomandibular joint with internal derangements and osteoarthrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002; 94: 515-21.

Nordahl S, Alstergren P, Kopp S. Tumor necrosis factor-alpha in synovial fluid and plasma from patients with chronic connective tissue disease and its relation to temporomandibular joint pain. J Oral Maxillofac Surg. 2000; 58: 525-30.

Emshoff R, Puffer P, Rudisch A, Gassner R. Temporomandibular joint pain: relationship to internal derangement type, osteoarthrosis, and synovial fluid mediator level of tumor necrosis factor-alpha. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000t; 90: 442-9.

Fang PK, Ma XC, Ma DL, Fu KY. Determination of interleukin-1 receptor antagonist, interleukin-10, and transforming growth factor-beta1 in synovial fluid aspirates of patients with temporomandibular disorders. J Oral Maxillofac Surg. 1999; 57: 922-9.

Takahashi T, Kondoh T, Fukuda M, Yamazaki Y, Toyosaki T, Suzuki R. Proinflammatory cytokines detectable in synovial fluids from patients with temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 85: 135-41.

Nishimura M, Segami N, Kaneyama K, Suzuki T, Miyamaru M. Proinflammatory cytokines and arthroscopic findings of patients with internal derangement and osteoarthritis of the temporomandibular joint. Br J Oral Maxillofac Surg. 2002; 40: 68-71.

Sandler NA, Buckley MJ, Cillo JE, Braun TW. Correlation of inflammatory cytokines with arthroscopic findings in patients with temporomandibular joint internal derangements. J Oral Maxillofac Surg. 1998; 56: 534-43.

Sato J, Segami N, Nishimura M, Demura N, Yoshimura H, Yoshitake Y, et al. Expression of interleukin 6 in synovial tissues in patients with internal derangement of the temporomandibular joint. Br J Oral Maxillofac Surg. 2003; 41: 95-101.

Kardel R, Ulfgren AK, Reinholt FP, Holmlund A. Inflammatory cell and cytokine patterns in patients with painful clicking and osteoarthritis in the temporomandibular joint. Int J Oral Maxillofac Surg. 2003; 32: 390-6.

Nordahl S, Alstergren P, Eliasson S, Kopp S. Interleukin- 1beta in plasma and synovial fluid in relation to radiographic changes in arthritic temporomandibular joints. Eur J Oral Sci. 1998; 106: 559-63.

Suzuki T, Segami N, Kaneyama K, Nishimura M, Nojima T. Specific expression of interleukin-1 beta in temporomandibular joints with internal derangement: correlation with clinical findings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999; 88: 413-7.

Alstergren P, Benavente C, Kopp S. Interleukin-1beta, interleukin-1 receptor antagonist, and interleukin-1 soluble receptor II in temporomandibular joint synovial fluid from patients with chronic polyarthritides. J Oral Maxillofac Surg. 2003; 61: 1171-8.

Malemud CJ. Fundamental pathways in osteoarthritis: an overview. Front Biosci. 1999; 4: 659-61.

Wiberg B, Wanman A. Signs of osteoarthrosis of the temporomandibular joints in young patients: a clinical and radiographic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998 ; 86: 158-64.

Suzuki T, Segami N, Nishimura M, Nojima T. Co-expression of interleukin-1beta and tumor necrosis factor alpha in synovial tissues and synovial fluids of temporomandibular joint with internal derangement: comparison with histological grading of synovial inflammation. J Oral Pathol Med. 2002; 31: 549-57.

Spears R, Oakes R, Moore C, Bellinger LL, Hutchins B. A determination of tumor necrosis factor expression in TMJ inflammation with the use of microarray analysis. J Dent Res. 2003; 82: 807-13.

Malyak M, Swaney RE, Arend WP. Levels of synovial fluid interleukin-1 receptor antagonist in rheumatoid arthritis and other arthropathies. Potential contribution from synovial fluid neutrophils. Arthritis Rheum. 1993; 36: 781-9.

Habu M, Tominaga K, Sukedai M, Alstergren P, Ohkawara S, Kopp S, Fukuda J. Immunohistochemical study of interleukin- 1beta and interleukin-1 receptor antagonist in an antigeninduced arthritis of the rabbit temporomandibular joint. J Oral Pathol Med. 2002; 31: 45-54.

Tobe M, Ogura N, Abiko Y, Nagura H. Interleukin-1beta stimulates interleukin-8 production and gene expression in synovial cells from human temporomandibular joint. J Oral Maxillofac Surg. 2002; 60: 741-7.

Ogura N, Tobe M, Sakamaki H, Kujiraoka H, Akiba M, Abiko Y et al. Interleukin-1 beta induces interleukin-6 mRNA expression and protein production in synovial cells from human temporomandibular joint. J Oral Pathol Med. 2002; 31: 353-60.

Spears R, Dees LA, Sapozhnikov M, Bellinger LL, Hutchins B. Temporal changes in inflammatory mediator concentrations in an adjuvant model of temporomandibular joint inflammation. J Orofac Pain. 2005; 19: 34-40.

Nishimura M, Segami N, Kaneyama K, Sato J, Fujimura K. Comparison of cytokine level in synovial fluid between successful and unsuccessful cases in arthrocentesis of the temporomandibular joint. J Oral Maxillofac Surg. 2004; 62: 284-7.

Kacena MA, Merrel GA, Konda SR, Wilson KM, Xi Y, Horowitz MC. Inflammation and bony changes at the temporomandibular joint. Cells Tissues Organs. 2001; 169: 257-64.

Malemud CJ, Goldberg VM. Future directions for research and treatment of osteoarthritis. Front Biosci. 1999; 4: 62-71.

Ulfgren AK, Grondal L, Lindblad S, Khademi M, Johnell O, Klareskog L et al. Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment. Ann Rheum Dis. 2000; 59: 439-47.

Thompson MW, McInnes RR, Willard HF. Thompson and Thompson genetics in medicine. 5th ed. Philadelphia: WB Saunders; 1991.

Stern AG, de Carvalho MR, Buck GA, Adler RA, Rao TP, Disler D, et al. Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartilage. 2003; 11: 394- 402.

Waldron-Lynch F, Adams C, Amos C, Zhu DK, McDermott MF, Shanahan F, et al. Tumour necrosis factor 5' promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun. 2001; 2: 82-7.

Moos V, Rudwaleit M, Herzog V, Hohlig K, Sieper J, Muller B. Association of genotypes affecting the expression of interleukin-1beta or interleukin-1 receptor antagonist with osteoarthritis. Arthritis Rheum. 2000; 43: 2417-22.

Pascual M, Nieto A, Mataran L, Balsa A, Pascual-Salcedo D, Martin J. IL-6 promoter polymorphisms in rheumatoid arthritis. Genes Immun. 2000; 1: 338-40.

Van Der Linden MW, Huizinga TW, Stoeken DJ, Sturk A, Westendorp RG. Determination of tumour necrosis factoralpha and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation. J Immunol Methods. 1998; 218: 63-71.

Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A. A Genetic influence on cytokine production in meningococcal disease. Lancet. 1997; 349: 1912-13.




How to Cite

Campos MIG, Campos PSF, Line SRP. Inflammatory cytokines activity in temporomandibular joint disorders: a review of literature. Braz. J. Oral Sci. [Internet]. 2015 Nov. 26 [cited 2022 Dec. 3];5(18):1054-62. Available from:



Literature Reviews

Most read articles by the same author(s)