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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Higher Levels of Serum TLR2 and TLR4 in Patients with Hashimoto's Thyroiditis

Author(s): Tugba Aktaş, Sevim K. Celik*, Gunes C. Genc, Dilek Arpaci, Murat Can and Ahmet Dursun

Volume 20, Issue 1, 2020

Page: [118 - 126] Pages: 9

DOI: 10.2174/1871530319666190329114621

Price: $65

Abstract

Objective: Hashimoto’s thyroiditis (HT) is an autoimmune disorder caused by the interaction between genes and environmental triggers. HT is the most common endocrine disorder, as well as the most common cause of hypothyroidism. Autoimmunity plays a crucial role in the pathogenesis of HT and recent studies suggest that Toll-like receptor (TLR) signals lead to increased inflammatory response. The aim of our study is to investigate whether TLR-2 and TLR-4 levels and gene polymorphisms contribute to the damaged immune response leading to HT.

Methods: Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms (SNPs) of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile were studied in 100 patients with HT and 100 healthy controls. Also, we investigated serum levels of TLR-2 and TLR-4 in the immunopathogenesis of HT. TLR-2 and TLR-4 serum levels were found to be significantly higher in HT patients than the control group. However, no statistical significance was found between patient and control groups in terms of genotype frequencies and allele frequency distribution of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphisms.

Result: TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphism do not appear to have a role in the development of HT disease. However, in our study, serum levels of TLR-2 and TLR-4 were found to be higher in HT patients than control groups.

Conclusion: These findings suggest that TLR-2 and TLR-4 play an important role in the immunopathologic mechanism of disease by causing an increase in proinflammatory response.

Keywords: Hashimoto’s thyroiditis, TLR2, TLR4, polymorphism, Arg677Trp, Arg753Gln, Asp299Gly.

Graphical Abstract
[1]
Hasham, A.; Tomer, Y. Genetic and epigenetic mechanisms in thyroid autoimmunity. Immunol. Res., 2012, 54(1-3), 204-213.
[http://dx.doi.org/10.1007/s12026-012-8302-x] [PMID: 22457094]
[2]
Chistiakov, D.A. Immunogenetics of Hashimoto’s thyroiditis. J. Autoimmune Dis., 2005, 2(1), 1.
[http://dx.doi.org/10.1186/1740-2557-2-1] [PMID: 15762980]
[3]
Bae, Y.S.; Lee, J.H.; Choi, S.H.; Kim, S.; Almazan, F.; Witztum, J.L.; Miller, Y.I. Macrophages generate reactive oxygen species in response to minimally oxidized LDL: TLR4-and Syk-dependent activation of Nox2. Circ. Res., 2009, 104(2), 210-218.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.181040] [PMID: 19096031]
[4]
Brown, J.; Wang, H.; Hajishengallis, G.N.; Martin, M. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J. Dent. Res., 2011, 90(4), 417-427.
[http://dx.doi.org/10.1177/0022034510381264] [PMID: 20940366]
[5]
Miyake, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol., 2007, 19(1), 3-10.
[http://dx.doi.org/10.1016/j.smim.2006.12.002] [PMID: 17275324]
[6]
Estruch, M.; Bancells, C.; Beloki, L.; Sanchez-Quesada, J.L.; Ordóñez-Llanos, J.; Benitez, S. CD14 and TLR4 mediate cytokine release promoted by electronegative LDL in monocytes. Atherosclerosis, 2013, 229(2), 356-362.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.05.011] [PMID: 23880187]
[7]
Sadanaga, A.; Nakashima, H.; Akahoshi, M.; Masutani, K.; Miyake, K.; Igawa, T.; Sugiyama, N.; Niiro, H.; Harada, M. Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum., 2007, 56(5), 1618-1628.
[http://dx.doi.org/10.1002/art.22571] [PMID: 17469144]
[8]
Xu, D.; Komai-Koma, M.; Liew, F.Y. Expression and function of Toll-like receptor on T cells. Cell. Immunol., 2005, 233(2), 85-89.
[http://dx.doi.org/10.1016/j.cellimm.2005.04.019] [PMID: 15950961]
[9]
Verstrepen, L.; Bekaert, T.; Chau, T.L.; Tavernier, J.; Chariot, A.; Beyaert, R. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell. Mol. Life Sci., 2008, 65(19), 2964-2978.
[http://dx.doi.org/10.1007/s00018-008-8064-8] [PMID: 18535784]
[10]
Toussi, D.N.; Massari, P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel), 2014, 2(2), 323-353.
[http://dx.doi.org/10.3390/vaccines2020323] [PMID: 26344622]
[11]
Kutikhin, A.G. Impact of Toll-like receptor 4 polymorphisms on risk of cancer. Hum. Immunol., 2011, 72(2), 193-206.
[http://dx.doi.org/10.1016/j.humimm.2010.11.003] [PMID: 21081146]
[12]
Liu, Y.; Yin, H.; Zhao, M.; Lu, Q. TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin. Rev. Allergy Immunol., 2014, 47(2), 136-147.
[http://dx.doi.org/10.1007/s12016-013-8402-y] [PMID: 24352680]
[13]
Kiechl, S.; Lorenz, E.; Reindl, M.; Wiedermann, C.J.; Oberhollenzer, F.; Bonora, E.; Willeit, J.; Schwartz, D.A. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med., 2002, 347(3), 185-192.
[http://dx.doi.org/10.1056/NEJMoa012673] [PMID: 12124407]
[14]
Lee, Y.H.; Bae, S.C.; Kim, J.H.; Song, G.G. Toll-like receptor polymorphisms and rheumatoid arthritis: a systematic review. Rheumatol. Int., 2014, 34(1), 111-116.
[http://dx.doi.org/10.1007/s00296-013-2666-7] [PMID: 23325096]
[15]
Garcia-Rodriguez, S.; Arias-Santiago, S.; Perandrés-López, R.; Castellote, L.; Zumaquero, E.; Navarro, P.; Buendía-Eisman, A.; Ruiz, J.C.; Orgaz-Molina, J.; Sancho, J.; M., Zubiaur Increased gene expression of Toll-like receptor 4 on peripheral blood mononuclear cells in patients with psoriasis. J. Eur. Acad. Dermatol. Venereol., 2013, 27(2), 242-250.
[http://dx.doi.org/10.1111/j.1468-3083.2011.04372.x] [PMID: 23457721]
[16]
Bustamante, M.F.; Fissolo, N.; Río, J.; Espejo, C.; Costa, C.; Mansilla, M.J.; Lizasoain, I.; Moro, M.A. Carmen, Edo, M.; Montalban, X.; Comabella, M. Implication of the Toll-likereceptor 4 pathway in the response to interferon-β in multiple sclerosis. Ann. Neurol., 2011, 70(4), 634-645.
[http://dx.doi.org/10.1002/ana.22511] [PMID: 22028223]
[17]
Shen, X.; Shi, R.; Zhang, H.; Li, K.; Zhao, Y.; Zhang, R. The Toll-like receptor 4 D299G and T399I polymorphisms are associated with Crohn’s disease and ulcerative colitis: a meta-analysis. Digestion, 2010, 81(2), 69-77.
[http://dx.doi.org/10.1159/000260417] [PMID: 20093834]
[18]
Takeuchi, O.; Hoshino, K.; Kawai, T.; Sanjo, H.; Takada, H.; Ogawa, T.; Takeda, K.; Akira, S. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity, 1999, 11(4), 443-451.
[http://dx.doi.org/10.1016/S1074-7613(00)80119-3] [PMID: 10549626]
[19]
Chen, Y.C.; Hsiao, C.C.; Chen, C.J. Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts. BMC Med. Genet., 2010, 30, 11-17.
[http://dx.doi.org/10.1186/1471-2350-11-17]
[20]
Noguchi, E.; Nishimura, F.; Fukai, H.; Kim, J.; Ichikawa, K.; Shibasaki, M.; Arinami, T. An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population. Clin. Exp. Allergy, 2004, 34(2), 177-183.
[http://dx.doi.org/10.1111/j.1365-2222.2004.01839.x] [PMID: 14987294]
[21]
Lorenz, E.; Mira, J.P.; Cornish, K.L.; Arbour, N.C.; Schwartz, D.A. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect. Immun., 2000, 68(11), 6398-6401.
[http://dx.doi.org/10.1128/IAI.68.11.6398-6401.2000] [PMID: 11035751]
[22]
Kang, T.J.; Chae, G.T. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol. Med. Microbiol., 2001, 31(1), 53-58.
[http://dx.doi.org/10.1111/j.1574-695X.2001.tb01586.x] [PMID: 11476982]
[23]
Aderem, A.; Ulevitch, R.J. Toll-like receptors in the induction of the innate immune response. Nature, 2000, 406(6797), 782-787.
[http://dx.doi.org/10.1038/35021228] [PMID: 10963608]
[24]
Rallabhandi, P.; Bell, J.; Boukhvalova, M.S.; Medvedev, A.; Lorenz, E.; Arditi, M.; Hemming, V.G.; Blanco, J.C.; Segal, D.M.; Vogel, S.N. Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J. Immunol., 2006, 177(1), 322-332.
[http://dx.doi.org/10.4049/jimmunol.177.1.322] [PMID: 16785528]
[25]
Arbour, N.C.; Lorenz, E.; Schutte, B.C.; Zabner, J.; Kline, J.N.; Jones, M.; Frees, K.; Watt, J.L.; Schwartz, D.A. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet., 2000, 25(2), 187-191.
[http://dx.doi.org/10.1038/76048] [PMID: 10835634]
[26]
Sim, N.L.; Kumar, P.; Hu, J.; Henikoff, S.; Schneider, G.; Ng, P.C. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res., 2012, 40(Web Server issue), W452-7.
[http://dx.doi.org/10.1093/nar/gks539] [PMID: 22689647]
[28]
Bland, J.M.; Altman, D.G. Multiple significance tests: the Bonferroni method. BMJ, 1995, 310(6973), 170.
[http://dx.doi.org/10.1136/bmj.310.6973.170] [PMID: 7833759]
[29]
Kumar, H.; Kawai, T.; Akira, S. Toll-like receptors and innate immunity. Biochem. Biophys. Res. Commun., 2009, 388(4), 621-625.
[http://dx.doi.org/10.1016/j.bbrc.2009.08.062] [PMID: 19686699]
[30]
Cho, W.K.; Jang, J.P.; Choi, E.J.; Jeon, Y.J.; Jung, I.A.; Kim, S.H.; Jung, M.H.; Kim, T.G.; Suh, B.K. Association of Toll-like receptor 10 polymorphisms with autoimmune thyroid disease in Korean children. Thyroid, 2015, 25(2), 250-255.
[http://dx.doi.org/10.1089/thy.2014.0135] [PMID: 25295614]
[31]
Inoue, N.; Katsumata, Y.; Watanabe, M.; Ishido, N.; Manabe, Y.; Watanabe, A.; Masutani, R.; Hidaka, Y.; Iwatani, Y. Polymorphisms and expression of toll-like receptors in autoimmune thyroid diseases. Autoimmunity, 2017, 50(3), 182-191.
[http://dx.doi.org/10.1080/08916934.2016.1261835] [PMID: 28013570]
[32]
Castiblanco, J.; Varela, D.C.; Castaño-Rodríguez, N.; Rojas-Villarraga, A.; Hincapié, M.E.; Anaya, J.M. TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus. Infect. Genet. Evol., 2008, 8(5), 541-544.
[http://dx.doi.org/10.1016/j.meegid.2008.03.001] [PMID: 18417424]
[33]
Boiardi, L.; Casali, B.; Farnetti, E.; Pipitone, N.; Nicoli, D.; Macchioni, P.; Cimino, L.; Bajocchi, G.L.; Catanoso, M.G.; Pattacini, L.; Ghinoi, A.; Restuccia, G.; Salvarani, C. Toll-like receptor 4 (TLR4) gene polymorphisms in giant cell arteritis. Clin. Exp. Rheumatol., 2009, 27(1)(Suppl. 52), S40-S44.
[PMID: 19646345]
[34]
Bacanli, A.; Sallakci, N.; Yavuzer, U.; Alpsoy, E.; Yegin, O. Toll-like receptor 2 Arg753Gln gene polymorphism in Turkish patients with Behçet’s disease. Clin. Exp. Dermatol., 2006, 31(5), 699-701.
[http://dx.doi.org/10.1111/j.1365-2230.2006.02212.x] [PMID: 16901312]
[35]
Coşan, F.; Oku, B.; Çakiris, A.; Duymaz-Tozkir, J.; Mercanoğlu, F.; Saruhan-Direskeneli, G.; Ustek, D.; Gül, A. No association of the TLR2 gene Arg753Gln polymorphism with rheumatic heart disease and Behçet’s disease. Clin. Rheumatol., 2009, 28(12), 1385-1388.
[http://dx.doi.org/10.1007/s10067-009-1252-6] [PMID: 19693643]
[36]
Radstake, T.R.; Roelofs, M.F.; Jenniskens, Y.M.; Oppers-Walgreen, B.; van Riel, P.L.; Barrera, P.; Joosten, L.A.; van den Berg, W.B. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-γ. Arthritis Rheum., 2004, 50(12), 3856-3865.
[http://dx.doi.org/10.1002/art.20678] [PMID: 15593217]
[37]
Kawakami, A.; Nakashima, K.; Tamai, M.; Nakamura, H.; Iwanaga, N.; Fujikawa, K.; Aramaki, T.; Arima, K.; Iwamoto, N.; Ichinose, K.; Kamachi, M.; Ida, H.; Origuchi, T.; Eguchi, K. Toll-like receptor in salivary glands from patients with Sjögren’s syndrome: functional analysis by human salivary gland cell line. J. Rheumatol., 2007, 34(5), 1019-1026.
[PMID: 17407216]
[38]
Shaw, P.J.; Barr, M.J.; Lukens, J.R.; McGargill, M.A.; Chi, H.; Mak, T.W.; Kanneganti, T.D. Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. Immunity, 2011, 34(1), 75-84.
[http://dx.doi.org/10.1016/j.immuni.2010.12.015] [PMID: 21236705]
[39]
Peng, S.; Li, C.; Wang, X.; Liu, X.; Han, C.; Jin, T.; Liu, S.; Zhang, X.; Zhang, H.; He, X.; Xie, X.; Yu, X.; Wang, C.; Shan, L.; Fan, C.; Shan, Z.; Teng, W. Increased Toll-Like Receptors Activity and TLR Ligands in Patients with Autoimmune Thyroid Diseases. Front. Immunol., 2016, 9(7), 578.
[http://dx.doi.org/10.3389/fimmu.2016.00578]
[40]
Kawashima, A.; Yamazaki, K.; Hara, T.; Akama, T.; Yoshihara, A.; Sue, M.; Tanigawa, K.; Wu, H.; Ishido, Y.; Takeshita, F.; Ishii, N.; Sato, K.; Suzuki, K. Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions. Thyroid, 2013, 23(4), 477-487.
[http://dx.doi.org/10.1089/thy.2011.0480] [PMID: 23234343]
[41]
Takeda, K.; Kaisho, T.; Akira, S. Toll-like receptors. Annu. Rev. Immunol., 2003, 21, 335-376.
[http://dx.doi.org/10.1146/annurev.immunol.21.120601.141126] [PMID: 12524386]
[42]
Figueroa-Vega, N.; Alfonso-Pérez, M.; Benedicto, I.; Sánchez-Madrid, F.; González-Amaro, R.; Marazuela, M. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J. Clin. Endocrinol. Metab., 2010, 95(2), 953-962.
[http://dx.doi.org/10.1210/jc.2009-1719] [PMID: 20016049]
[43]
Zhang, J.A.; Zhang, J.; Xu, L.; Mar, H.; Wu, X.Y. Measurement of IL-12 and IL-18 in sera of patients with autoimmune thyroid disease. Xi bao yu fen zi mian yi xue za zhi., 2006, 22(5), 630-632.
[44]
Guo, H.; Peng, D.; Yang, X.G.; Wang, Y.; Xu, B.C.; Ni, J.S.; Meng, W.; Jiang, Y.F. A higher frequency of circulating IL-22(+)CD4(+) T cells in Chinese patients with newly diagnosed Hashimoto’s thyroiditis. PLoS One, 2014, 9(1)e84545
[http://dx.doi.org/10.1371/journal.pone.0084545] [PMID: 24404171]
[45]
Liu, R.; Mo, Y.Y.; Wang, H.L.; Tan, Y.; Wen, X.J.; Deng, M.J.; Yan, H.; Li, L. The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis. Sci. Rep., 2016, 6, 38947.
[http://dx.doi.org/10.1038/srep38947] [PMID: 27958344]
[46]
Joosten, L.A.; Abdollahi-Roodsaz, S.; Dinarello, C.A.; O’Neill, L.; Netea, M.G. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat. Rev. Rheumatol., 2016, 12(6), 344-357.
[http://dx.doi.org/10.1038/nrrheum.2016.61] [PMID: 27170508]

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