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Endocrine, Metabolic & Immune Disorders - Drug Targets

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

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Research Article

Caveolin-1 Regulates CCL5 and PPARγ Expression in Nthy-ori 3-1 Cells: Possible Involvement of Caveolin-1 and CCL5 in the Pathogenesis of Hashimoto’s Thyroiditis

Author(s): Baocui Liu, Tingting Zheng, Liyang Dong, Chaoming Mao*, Chengcheng Xu, Xiao Mou, Xuan Luo, Qingyan Lu, Xin Dong, Jiameng Liu, Ping Kang, Chao Ding, Yichuan Xiao and Peng Jiang*

Volume 20, Issue 4, 2020

Page: [609 - 618] Pages: 10

DOI: 10.2174/1871530319666191202115149

Price: $65

Abstract

Background: Hashimoto’s thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid parenchyma, which ultimately leads to tissue destruction and loss of function. Caveolin-1 (Cav-1) is an essential structural constituent of lipid rafts in the plasma membrane of cells and is reported to be significantly reduced in thyrocytes from HT patients. However, the mechanism of Cav-1 involvement in HT pathogenesis is still largely unclear.

Methods: Cav-1 expression in thyroid tissues from HT patients and euthyroid nodular goiter tissues was detected by immunohistochemistry staining. Cav-1 knockdown and overexpression were constructed by lentiviral transfection in the human thyroid follicular epithelial cell (TFC) line of Nthy-ori 3-1. The mRNA expression levels of chemokines in TFCs were determined by quantitative real-time PCR (qPCR). Cav-1 and peroxisome proliferator-activated receptor gamma (PPARγ) levels were analysed by qPCR and Western blot analysis. The migration ability of peripheral blood mononuclear cells (PBMCs) was detected by the Transwell assay.

Results: In this study, Cav-1 and PPARγ expression was reduced in the thyroid tissues from HT patients. In vitro experiments showed that the expressions of chemokine (C-C motif) ligand 5 (CCL5) and migration of PBMCs were markedly increased, while the level of PPARγ was significantly decreased after the lentivirus-mediated knockdown of Cav-1 in Nthy-ori 3-1 cells. Interestingly, pioglitazone, a PPARγ agonist, not only upregulated PPARγ and Cav-1 proteins significantly, but also effectively reversed the Cav-1-knockdown-induced upregulation of CCL5 in Nthy-ori 3-1 cells and reduced the infiltration of lymphocytes.

Conclusion: The inhibition of Cav-1 upregulated the CCL5 expression and downregulated the PPARγ expression in TFC while pioglitazone, a PPARγ agonist, reversed the detrimental consequence. This outcome might be a potential target for the treatment of lymphocyte infiltration into the thyroid gland and HT development.

Keywords: Hashimoto’s thyroiditis, Cav-1, Chemokine, CCL5, PPARγ, Pioglitazone

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[1]
Antonelli, A.; Ferrari, S.M.; Corrado, A.; Di Domenicantonio, A.; Fallahi, P. Autoimmune thyroid disorders. Autoimmun. Rev., 2015, 14(2), 174-180.
[http://dx.doi.org/10.1016/j.autrev.2014.10.016] [PMID: 25461470]
[2]
Golden, S.H.; Robinson, K.A.; Saldanha, I.; Anton, B.; Ladenson, P.W. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J. Clin. Endocrinol. Metab., 2009, 94(6), 1853-1878.
[http://dx.doi.org/10.1210/jc.2008-2291] [PMID: 19494161]
[3]
Liu, H.; Zheng, T.; Mao, Y.; Xu, C.; Wu, F.; Bu, L.; Mou, X.; Zhou, Y.; Yuan, G.; Wang, S.; Zhou, T.; Chen, D.; Mao, C. γδ Τ cells enhance B cells for antibody production in Hashimoto’s thyroiditis, and retinoic acid induces apoptosis of the γδ Τ cell. Endocrine, 2016, 51(1), 113-122.
[http://dx.doi.org/10.1007/s12020-015-0631-9] [PMID: 25994301]
[4]
Weetman, A.P. Autoimmune thyroid disease: propagation and progression. Eur. J. Endocrinol., 2003, 148(1), 1-9.
[http://dx.doi.org/10.1530/eje.0.1480001] [PMID: 12534350]
[5]
Bhatia, A.; Rajwanshi, A.; Dash, R.J.; Mittal, B.R.; Saxena, A.K. Lymphocytic thyroiditis--is cytological grading significant? A correlation of grades with clinical, biochemical, ultrasonographic and radionuclide parameters. Cytojournal, 2007, 4, 10.
[http://dx.doi.org/10.1186/1742-6413-4-10] [PMID: 17470291]
[6]
Anila, K.R.; Nayak, N.; Jayasree, K. Cytomorphologic spectrum of lymphocytic thyroiditis and correlation between cytological grading and biochemical parameters. J. Cytol., 2016, 33(3), 145-149.
[http://dx.doi.org/10.4103/0970-9371.188055] [PMID: 27756987]
[7]
Wang, X.X.; Wu, Z.; Huang, H.F.; Han, C.; Zou, W.; Liu, J. Caveolin-1, through its ability to negatively regulate TLR4, is a crucial determinant of MAPK activation in LPS-challenged mammary epithelial cells. Asian Pac. J. Cancer Prev., 2013, 14(4), 2295-2299.
[http://dx.doi.org/10.7314/APJCP.2013.14.4.2295] [PMID: 23725130]
[8]
Zhang, X.; Shen, P.; Coleman, M.; Zou, W.; Loggie, B.W.; Smith, L.M.; Wang, Z. Caveolin-1 down-regulation activates estrogen receptor alpha expression and leads to 17beta-estradiol-stimulated mammary tumorigenesis. Anticancer Res., 2005, 25(1A), 369-375.
[PMID: 15816560]
[9]
Song, Y.; Driessens, N.; Costa, M.; De Deken, X.; Detours, V.; Corvilain, B.; Maenhaut, C.; Miot, F.; Van Sande, J.; Many, M.C.; Dumont, J.E. Roles of hydrogen peroxide in thyroid physiology and disease. J. Clin. Endocrinol. Metab., 2007, 92(10), 3764-3773.
[http://dx.doi.org/10.1210/jc.2007-0660] [PMID: 17666482]
[10]
Marique, L.; Van Regemorter, V.; Gérard, A.C.; Craps, J.; Senou, M.; Marbaix, E.; Rahier, J.; Daumerie, C.; Mourad, M.; Lengelé, B.; Colin, I.M.; Many, M.C. The expression of dual oxidase, thyroid peroxidase, and caveolin-1 differs according to the type of immune response (TH1/TH2) involved in thyroid autoimmune disorders. J. Clin. Endocrinol. Metab., 2014, 99(5), 1722-1732.
[http://dx.doi.org/10.1210/jc.2013-3469] [PMID: 24476075]
[11]
Senou, M.; Costa, M.J.; Massart, C.; Thimmesch, M.; Khalifa, C.; Poncin, S.; Boucquey, M.; Gérard, A.C.; Audinot, J.N.; Dessy, C.; Ruf, J.; Feron, O.; Devuyst, O.; Guiot, Y.; Dumont, J.E.; Van Sande, J.; Many, M.C. Role of caveolin-1 in thyroid phenotype, cell homeostasis, and hormone synthesis: in vivo study of caveolin-1 knockout mice. Am. J. Physiol. Endocrinol. Metab., 2009, 297(2), E438-E451.
[http://dx.doi.org/10.1152/ajpendo.90784.2008] [PMID: 19435853]
[12]
Lu, Q.; Luo, X.; Mao, C.; Zheng, T.; Liu, B.; Dong, X.; Zhou, Y.; Xu, C.; Mou, X.; Wu, F.; Bu, L.; Yuan, G. Caveolin-1 regulates autophagy activity in thyroid follicular cells and is involved in Hashimoto’s thyroiditis disease. Endocr. J., 2018, 65(9), 893-901.
[http://dx.doi.org/10.1507/endocrj.EJ18-0003] [PMID: 29877208]
[13]
Zlotnik, A.; Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity, 2000, 12(2), 121-127.
[http://dx.doi.org/10.1016/S1074-7613(00)80165-X] [PMID: 10714678]
[14]
Nie, X.; Tan, J.; Dai, Y.; Liu, Y.; Zou, J.; Sun, J.; Ye, S.; Shen, C.; Fan, L.; Chen, J.; Bian, J.S. CCL5 deficiency rescues pulmonary vascular dysfunction, and reverses pulmonary hypertension via caveolin-1-dependent BMPR2 activation. J. Mol. Cell. Cardiol., 2018, 116(116), 41-56.
[http://dx.doi.org/10.1016/j.yjmcc.2018.01.016] [PMID: 29374556]
[15]
Kimura, H.; Caturegli, P. Chemokine orchestration of autoimmune thyroiditis. Thyroid, 2007, 17(10), 1005-1011.
[http://dx.doi.org/10.1089/thy.2007.0267] [PMID: 17910527]
[16]
García-López, M.A.; Sancho, D.; Sánchez-Madrid, F.; Marazuela, M. Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes. J. Clin. Endocrinol. Metab., 2001, 86(10), 5008-5016.
[http://dx.doi.org/10.1210/jcem.86.10.7953] [PMID: 11600578]
[17]
Kemp, E.H.; Metcalfe, R.A.; Smith, K.A.; Woodroofe, M.N.; Watson, P.F.; Weetman, A.P. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clin. Endocrinol. (Oxf.), 2003, 59(2), 207-213.
[http://dx.doi.org/10.1046/j.1365-2265.2003.01824.x] [PMID: 12864798]
[18]
Shen, X.J.; Zhang, H.; Tang, G.S.; Wang, X.D.; Zheng, R.; Wang, Y.; Zhu, Y.; Xue, X.C.; Bi, J.W. Caveolin-1 is a modulator of fibroblast activation and a potential biomarker for gastric cancer. Int. J. Biol. Sci., 2015, 11(4), 370-379.
[http://dx.doi.org/10.7150/ijbs.10666] [PMID: 25798057]
[19]
Xu, C.; Wu, F.; Mao, C.; Wang, X.; Zheng, T.; Bu, L.; Mou, X.; Zhou, Y.; Yuan, G.; Wang, S.; Xiao, Y. Excess iodine promotes apoptosis of thyroid follicular epithelial cells by inducing autophagy suppression and is associated with Hashimoto thyroiditis disease. J. Autoimmun., 2016, 75, 50-57.
[http://dx.doi.org/10.1016/j.jaut.2016.07.008] [PMID: 27448770]
[20]
Zheng, T.; Xu, C.; Mao, C.; Mou, X.; Wu, F.; Wang, X.; Bu, L.; Zhou, Y.; Luo, X.; Lu, Q.; Liu, H.; Yuan, G.; Wang, S.; Chen, D.; Xiao, Y. Increased Interleukin-23 in Hashimoto’s Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation. Front. Immunol., 2018, 9, 96.
[http://dx.doi.org/10.3389/fimmu.2018.00096] [PMID: 29434604]
[21]
Chen, M.P.; Chung, F.M.; Chang, D.M.; Tsai, J.C.; Huang, H.F.; Shin, S.J.; Lee, Y.J. Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab., 2006, 91(1), 295-299.
[http://dx.doi.org/10.1210/jc.2005-1475] [PMID: 16234302]
[22]
Werion, A.; Joris, V.; Hepp, M.; Papasokrati, L.; Marique, L.; de Ville de Goyet, C.; Van Regemorter, V.; Mourad, M.; Lengelé, B.; Daumerie, C.; Marbaix, E.; Brichard, S.; Many, M.C.; Craps, J. Pioglitazone, a PPARγ Agonist, Upregulates the Expression of Caveolin-1 and Catalase, Essential for Thyroid Cell Homeostasis: A Clue to the Pathogenesis of Hashimoto’s Thyroiditis. Thyroid, 2016, 26(9), 1320-1331.
[http://dx.doi.org/10.1089/thy.2015.0625] [PMID: 27324467]
[23]
Kim, B.A.; Jee, H.G.; Yi, J.W.; Kim, S.J.; Chai, Y.J.; Choi, J.Y.; Lee, K.E. Expression Profiling of a Human Thyroid Cell Line Stably Expressing the BRAFV600E Mutation. Cancer Genomics Proteomics, 2017, 14(1), 53-67.
[http://dx.doi.org/10.21873/cgp.20018] [PMID: 28031237]
[24]
Lemoine, N.R.; Mayall, E.S.; Jones, T.; Sheer, D.; McDermid, S.; Kendall-Taylor, P.; Wynford-Thomas, D. Characterisation of human thyroid epithelial cells immortalised in vitro by simian virus 40 DNA transfection. Br. J. Cancer, 1989, 60(6), 897-903.
[http://dx.doi.org/10.1038/bjc.1989.387] [PMID: 2557880]
[25]
Michalik, L.; Desvergne, B.; Wahli, W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat. Rev. Cancer, 2004, 4(1), 61-70.
[http://dx.doi.org/10.1038/nrc1254] [PMID: 14708026]
[26]
Nebbaki, S.S.; El Mansouri, F.E.; Afif, H.; Kapoor, M.; Benderdour, M.; Duval, N.; Pelletier, J.P.; Martel-Pelletier, J.; Fahmi, H. Egr-1 contributes to IL-1-mediated down-regulation of peroxisome proliferator-activated receptor γ expression in human osteoarthritic chondrocytes. Arthritis Res. Ther., 2012, 14(2), R69.
[http://dx.doi.org/10.1186/ar3788] [PMID: 22455954]
[27]
Burgermeister, E.; Friedrich, T.; Hitkova, I.; Regel, I.; Einwächter, H.; Zimmermann, W.; Röcken, C.; Perren, A.; Wright, M.B.; Schmid, R.M.; Seger, R.; Ebert, M.P. The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain. Mol. Cell. Biol., 2011, 31(16), 3497-3510.
[http://dx.doi.org/10.1128/MCB.01421-10] [PMID: 21690289]
[28]
Fallahi, P.; Ferrari, S.M.; Corrado, A.; Giuggioli, D.; Ferri, C.; Antonelli, A. Targeting chemokine (C-X-C motif) receptor 3 in thyroid autoimmunity. Recent Pat. Endocr. Metab. Immune Drug Discov., 2014, 8(2), 95-101.
[http://dx.doi.org/10.2174/1872214808666140623114315] [PMID: 24953644]
[29]
Antonelli, A.; Ferrari, S.M.; Mancusi, C.; Mazzi, V.; Pupilli, C.; Centanni, M.; Ferri, C.; Ferrannini, E.; Fallahi, P. Interferon-α, -β and -γ induce CXCL11 secretion in human thyrocytes: modulation by peroxisome proliferator-activated receptor γ agonists. Immunobiology, 2013, 218(5), 690-695.
[http://dx.doi.org/10.1016/j.imbio.2012.08.267] [PMID: 22944249]
[30]
Rogue, A.; Spire, C.; Brun, M.; Claude, N.; Guillouzo, A. Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver. PPAR Res., 2010, 2010 325183
[http://dx.doi.org/10.1155/2010/325183] [PMID: 20981297]
[31]
Rebuffat, S.A.; Kammoun-Krichen, M.; Charfeddine, I.; Ayadi, H.; Bougacha-Elleuch, N.; Peraldi-Roux, S. IL-1β and TSH disturb thyroid epithelium integrity in autoimmune thyroid diseases. Immunobiology, 2013, 218(3), 285-291.
[http://dx.doi.org/10.1016/j.imbio.2012.05.016] [PMID: 22878044]
[32]
Pyzik, A.; Grywalska, E.; Matyjaszek-Matuszek, B.; Roliński, J. Immune disorders in Hashimoto’s thyroiditis: what do we know so far? J. Immunol. Res., 2015, 2015 979167
[http://dx.doi.org/10.1155/2015/979167] [PMID: 26000316]
[33]
Phenekos, C.; Vryonidou, A.; Gritzapis, A.D.; Baxevanis, C.N.; Goula, M.; Papamichail, M. Th1 and Th2 serum cytokine profiles characterize patients with Hashimoto’s thyroiditis (Th1) and Graves’ disease (Th2). Neuroimmunomodulation, 2004, 11(4), 209-213.
[http://dx.doi.org/10.1159/000078438] [PMID: 15249726]
[34]
Ajjan, R.A.; Watson, P.F.; Weetman, A.P. Cytokines and thyroid function. Adv. Neuroimmunol., 1996, 6(4), 359-386.
[http://dx.doi.org/10.1016/S0960-5428(97)00027-7] [PMID: 9183517]
[35]
Giordano, C.; Stassi, G.; De Maria, R.; Todaro, M.; Richiusa, P.; Papoff, G.; Ruberti, G.; Bagnasco, M.; Testi, R.; Galluzzo, A. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science, 1997, 275(5302), 960-963.
[http://dx.doi.org/10.1126/science.275.5302.960] [PMID: 9020075]
[36]
Friedrich, T.; Richter, B.; Gaiser, T.; Weiss, C.; Janssen, K.P.; Einwächter, H.; Schmid, R.M.; Ebert, M.P.; Burgermeister, E. Deficiency of caveolin-1 in Apc(min/+) mice promotes colorectal tumorigenesis. Carcinogenesis, 2013, 34(9), 2109-2118.
[http://dx.doi.org/10.1093/carcin/bgt142] [PMID: 23640045]
[37]
Chidlow, J.H., Jr; Sessa, W.C. Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc. Res., 2010, 86(2), 219-225.
[http://dx.doi.org/10.1093/cvr/cvq075] [PMID: 20202978]
[38]
Martinez-Outschoorn, U.E.; Whitaker-Menezes, D.; Lin, Z.; Flomenberg, N.; Howell, A.; Pestell, R.G.; Lisanti, M.P.; Sotgia, F. Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle, 2011, 10(11), 1784-1793.
[http://dx.doi.org/10.4161/cc.10.11.15674] [PMID: 21566463]
[39]
Mackay, C.R. Chemokines: what chemokine is that? Curr. Biol., 1997, 7(6), R384-R386.
[http://dx.doi.org/10.1016/S0960-9822(06)00181-3] [PMID: 9197234]
[40]
Zlotnik, A.; Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity, 2000, 12(2), 121-127.
[http://dx.doi.org/10.1016/S1074-7613(00)80165-X] [PMID: 10714678]
[41]
Gu, X.; Zheng, L.; Chen, X.; Ruan, L.; Zhang, H.; Ge, S.; Zhu, H.; Lin, X.; Shen, F. Elevated serum IL-16 and RANTES levels in patients with autoimmune thyroid diseases and modulation by methimazole therapy. Horm. Metab. Res., 2012, 44(6), 482-487.
[http://dx.doi.org/10.1055/s-0032-1308973] [PMID: 22473756]
[42]
Tontonoz, P.; Hu, E.; Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell, 1994, 79(7), 1147-1156.
[http://dx.doi.org/10.1016/0092-8674(94)90006-X] [PMID: 8001151]
[43]
Rosen, E.D.; Sarraf, P.; Troy, A.E.; Bradwin, G.; Moore, K.; Milstone, D.S.; Spiegelman, B.M.; Mortensen, R.M. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell, 1999, 4(4), 611-617.
[http://dx.doi.org/10.1016/S1097-2765(00)80211-7] [PMID: 10549292]
[44]
Barroso, I.; Gurnell, M.; Crowley, V.E.; Agostini, M.; Schwabe, J.W.; Soos, M.A.; Maslen, G.L.; Williams, T.D.; Lewis, H.; Schafer, A.J.; Chatterjee, V.K.; O’Rahilly, S. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature, 1999, 402(6764), 880-883.
[http://dx.doi.org/10.1038/47254] [PMID: 10622252]
[45]
Lehrke, M.; Lazar, M.A. The many faces of PPARgamma. Cell, 2005, 123(6), 993-999.
[http://dx.doi.org/10.1016/j.cell.2005.11.026] [PMID: 16360030]
[46]
Llaverias, G.; Vázquez-Carrera, M.; Sánchez, R.M.; Noé, V.; Ciudad, C.J.; Laguna, J.C.; Alegret, M. Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. J. Lipid Res., 2004, 45(11), 2015-2024.
[http://dx.doi.org/10.1194/jlr.M400049-JLR200] [PMID: 15314095]
[47]
Tencer, L.; Burgermeister, E.; Ebert, M.P.; Liscovitch, M. Rosiglitazone induces caveolin-1 by PPARgamma-dependent and PPRE-independent mechanisms: the role of EGF receptor signaling and its effect on cancer cell drug resistance. Anticancer Res., 2008, 28(2A), 895-906.
[PMID: 18507034]
[48]
Lei, P.; Abdelrahim, M.; Cho, S.D.; Liu, S.; Chintharlapalli, S.; Safe, S. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase. Carcinogenesis, 2008, 29(6), 1139-1147.
[http://dx.doi.org/10.1093/carcin/bgn103] [PMID: 18460448]
[49]
Burgermeister, E.; Tencer, L.; Liscovitch, M. Peroxisome proliferator-activated receptor-gamma upregulates caveolin-1 and caveolin-2 expression in human carcinoma cells. Oncogene, 2003, 22(25), 3888-3900.
[http://dx.doi.org/10.1038/sj.onc.1206625] [PMID: 12813462]

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