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http://dx.doi.org/10.4062/biomolther.2014.042

Ciglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Inhibits Proliferation and Differentiation of Th17 Cells  

Kim, Dong Hyeok (Division of Applied Life Science, Gyeongsang National University)
Ihn, Hyun-Ju (Division of Applied Life Science, Gyeongsang National University)
Moon, Chaerin (Division of Applied Life Science, Gyeongsang National University)
Oh, Sang-Seok (Division of Applied Life Science, Gyeongsang National University)
Park, Soojong (Division of Applied Life Science, Gyeongsang National University)
Kim, Suk (College of Veterinary Medicine, Gyeongsang National University)
Lee, Keun Woo (Division of Applied Life Science, Gyeongsang National University)
Kim, Kwang Dong (Division of Applied Life Science, Gyeongsang National University)
Publication Information
Biomolecules & Therapeutics / v.23, no.1, 2015 , pp. 71-76 More about this Journal
Abstract
Peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) was identified as a cell-intrinsic regulator of Th17 cell differentiation. Th17 cells have been associated with several autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease (IBD), and collagen-induced arthritis. In this study, we confirmed $PPAR{\gamma}$-mediated inhibition of Th17 cell differentiation and cytokine production at an early stage. Treatment with ciglitazone, a $PPAR{\gamma}$ ligand, reduced both IL-$1{\beta}$-mediated enhancement of Th17 differentiation and activation of Th17 cells after polarization. For Th17 cell differentiation, we found that ciglitazone-treated cells had a relatively low proliferative activity and produced a lower amount of cytokines, regardless of the presence of IL-$1{\beta}$. The inhibitory activity of ciglitazone might be due to decrease of CCNB1 expression, which regulates the cell cycle in T cells. Hence, we postulate that a pharmaceutical $PPAR{\gamma}$ activator might be a potent candidate for treatment of Th17-mediated autoimmune disease patients.
Keywords
Th17 cell; IL-17; $PPAR{\gamma}$; CCNB1; Cell proliferation;
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1 Ahmad, S. F., Zoheir, K. M., Abdel-Hamied, H. E., Attia, S. M., Bakheet, S. A., Ashour, A. E. and Abd-Allah, A. R. (2014) Grape seed proanthocyanidin extract protects against carrageenan-induced lung inflammation in mice through reduction of pro-inflammatory markers and chemokine expressions. Inflammation 37, 500-511   DOI
2 Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M. and Evans, R. M. (2013) PPARg signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557-566.
3 Becher, B. and Segal, B. M. (2011) T(H)17 cytokines in autoimmune neuro-inflammation. Curr. Opin. Immunol. 23, 707-712.   DOI
4 Chung, Y., Chang, S. H., Martinez, G. J., Yang, X. O., Nurieva, R., Kang, H. S., Ma, L., Watowich, S. S., Jetten, A. M., Tian, Q. and Dong, C. (2009). Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576-587.   DOI
5 Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A. and Sedg- wick, J. D. (2003). Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744-748.   DOI
6 Diab, A., Deng, C., Smith, J. D., Hussain, R. Z., Phanavanh, B., Lovett-Racke, A. E., Drew, P. D. and Racke, M. K. (2002). Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy- Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 168, 2508-2515.   DOI
7 Evans, R. M., Barish, G. D. and Wang, Y. X. (2004). PPARs and the complex journey to obesity. Nat. Med. 10, 355-361.   DOI
8 Gazit, V., Huang, J., Weymann, A. and Rudnick, D. A. (2012) Analysis of the role of hepatic PPARg expression during mouse liver regeneration. Hepatology 56, 1489-1498.   DOI
9 Guri, A. J., Mohapatra, S. K., Horne, W. T., 2nd, Hontecillas, R. and Bassaganya-Riera, J. (2010) The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease. BMC Gastroenterol. 10, 60.   DOI
10 Hontecillas, R. and Bassaganya-Riera, J. (2007). Peroxisome proliferator- activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J. Immunol. 178, 2940-2949.   DOI
11 Klotz, L. and Knolle, P. (2011) Nuclear receptors: Th17 cell control from within. FEBS Lett. 585, 3764-3769.   DOI
12 Huang, J. T., Welch, J. S., Ricote, M., Binder, C. J., Willson, T. M., Kelly, C., Witztum, J. L., Funk, C. D., Conrad, D. and Glass, C. K. (1999). Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378-382.   DOI
13 Hwang, E. S. (2010) Transcriptional regulation of T helper 17 cell differentiation. Yonsei Med. J. 51, 484-491.   DOI
14 Klotz, L., Dani, I., Edenhofer, F., Nolden, L., Evert, B., Paul, B., Kolanus, W., Klockgether, T., Knolle, P. and Diehl, L. (2007). Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. J. Immunol. 178, 2122-2131.   DOI
15 Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Nowak, N., Beyer, M., Mayer, G., Langhans, B., Klockgether, T., Waisman, A., Eberl, G., Schultze, J., Famulok, M., Kolanus, W., Glass, C., Kurts and Knolle, P. A. (2009). The nuclear receptor PPARg selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 20, 2079-2089.
16 Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S. J., Oksenberg, J. R., Raine, C. S., Heller, R. and Steinman, L. (2002). Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500-508.   DOI
17 Newcomb, D. C. and Peebles, R. S., Jr. (2013) Th17-mediated inflammation in asthma. Curr. Opin. Immunol. 25, 755-760.   DOI
18 Moran-Salvador, E., Lopez-Parra, M., Garcia-Alonso, V., Titos, E., Martinez-Clemente, M., Gonzalez-Periz, A., Lopez-Vicario, C., Barak, Y., Arroyo, V. and Claria, J. (2011) Role for PPARg in obesity- induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 25, 2538-2550.   DOI
19 Murphy, C. A., Langrish, C. L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R. A., Sedgwick, J. D. and Cua, D. J. (2003). Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951-1957.   DOI
20 Mwinyi, J., Grete-Wenger, C., Eloranta, J. J. and Kullak-Ublick, G. A. (2012) The impact of PPARg genetic variants on IBD susceptibility and IBD disease course. PPAR Res. 2012, 349469.
21 Niino, M., Iwabuchi, K., Kikuchi, S., Ato, M., Morohashi, T., Ogata, A., Tashiro, K. and Onoe, K. (2001) Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-gamma. J. Neuroimmunol. 116, 40-48.   DOI
22 Rossi, M. and Bot, A. (2013) The Th17 cell population and the immune homeostasis of the gastrointestinal tract. Int. Rev. Immunol. 32, 471-474.   DOI
23 Schmidt, M. V., Brune, B. and von Knethen, A. (2010) The nuclear hormone receptor PPARgamma as a therapeutic target in major diseases. ScientificWorldJournal 10, 2181-2197.   DOI
24 Strakova, N., Ehrmann, J., Dzubak, P., Bouchal, J. and Kolar, Z. (2004). The synthetic ligand of peroxisome proliferator-activated receptor-gamma ciglitazone affects human glioblastoma cell lines. J. Pharmacol. Exp. Ther. 309, 1239-1247.   DOI
25 Tzartos, J. S., Friese, M. A., Craner, M. J., Palace, J., Newcombe, J., Esiri, M. M. and Fugger, L. (2008). Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172, 146-155.   DOI
26 Straus, D. S. and Glass, C. K. (2007). Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28, 551-558.   DOI
27 Szatmari, I., Torocsik, D., Agostini, M., Nagy, T., Gurnell, M., Barta, E., Chatterjee, K. and Nagy, L. (2007). PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110, 3271-3280.   DOI
28 Tontonoz, P. and Spiegelman, B. M. (2008). Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem. 77, 289-312.   DOI
29 Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Shah, B., Panopoulos, A. D., Schluns, K. S., Watowich, S. S., Tian, Q., Jetten, A. M. and Dong, C. (2008). T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28, 29-39.   DOI
30 Yeh, S. L., Yeh, C. L., Chan, S. T. and Chuang, C. H. (2011) Plasma rich in quercetin metabolites induces G2/M arrest by upregulating PPAR-gamma expression in human A549 lung cancer cells. Planta Med. 77, 992-998.   DOI
31 Yen, D., Cheung, J., Scheerens, H., Poulet, F., McClanahan, T., McKenzie, B., Kleinschek, M. A., Owyang, A., Mattson, J., Blumenschein, W., Murphy, E., Sathe, M., Cua, D. J., Kastelein, R. A. and Rennick, D. (2006). IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310-1316.   DOI