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系統識別號 U0026-0308201503050200
論文名稱(中文) PPARγ缺失所導致免疫失調
論文名稱(英文) Immune disturbance caused by PPARγ deficiency
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 劉雅惠
研究生(英文) Ya-Hui Liu
學號 S58971219
學位類別 博士
語文別 英文
論文頁數 82頁
口試委員 指導教授-蔡佩珍
召集委員-林以行
口試委員-蔡曜聲
口試委員-謝奇璋
口試委員-廖南詩
口試委員-許秉寧
口試委員-詹明修
中文關鍵字 過氧化物酶增生因子活化受體γ  脾臟肥大  Th17  B細胞活化  自體免疫 
英文關鍵字 PPARγ  splenomegaly  Th17  B cell activation  autoimmunity 
學科別分類
中文摘要 代謝以及自體免疫疾病的發生在工業國家有大幅增加的情況,這當中似乎有個共通因子能同時調節代謝以及自體免疫的平衡。過氧化物酶增生因子活化受體γ (PPARγ) 是能被配位體所激活的核內轉錄因子並且調控了許多的代謝路徑,包含脂質的生合成、醣類的代謝以及發炎反應。然而在生物體內,PPARγ 參與在免疫平衡的角色上仍然未被完全了解。表達25% PPARγ 的模式小鼠 (PpargC/-小鼠)在14 個月大的年齡具有高量的抗dsDNA 抗體、抗核抗體以及免疫沉積物堆積在腎絲球體中,發展出類紅斑性狼瘡的自體免疫疾病。而在這些症狀之前,年紀輕的時候就有脾臟腫大的現象,為脾臟細胞聚集數量增加以及B 淋巴細胞活化所致,而非造血作用轉移到脾臟所造成。此外PpargC/-小鼠的脾臟細胞其sphingosine-1-phosphate receptor 1 (S1P1)的表達量下降,妨礙了淋巴細胞外出可能是聚集在脾臟的機制之一。而在機制上,發現Th17 的極性以及IL-17 的訊息傳遞在PpargC/- CD4+ T 淋巴細胞都有增加的情形,說明了在生物體內的微環境下PPARγ 低表達量的CD4+ T 淋巴細胞在脾臟能調節B 淋巴細胞的過度活化。最後,利用給予piolitazone 的方式活化僅剩的PPARγ 能夠增加S1P1 的表現量、降低Th17 在脾臟的量以及減緩脾臟肥大的情形。總言,我們的研究證實在 T 淋巴細胞內Pparg 表量的下降是個重要的因子造成自發性類紅斑性狼瘡自體免疫疾病的發生,並且發現PPARγ 的新角色在淋巴細胞的移行以及參與在Th17 和B淋巴細胞的對話。
英文摘要 Metabolism and autoimmune disease have experienced a dramatic increase in industrialized countries. A common factor regulating both metabolic and autoimmune balance is suggested. PPARγ is a nuclear transcription factor that modulates diverse functions, including lipid biosynthesis, glucose metabolism and inflammation. However, its specific role in the balance of immunity in vivo has not been fully explored. PpargC/- mice expressing PPARγ at 25% normal level exhibited higher levels of autoantibodies and developed lupus nephritis, resembling the development of a lupus-like autoimmune syndrome by 14 months of age. These symptoms are preceded by splenomegaly in the early age, which is associated with increases of splenocyte accumulation and B-cell activation, but not relocation of hematopoiesis to the spleen. Reduced expression of sphingosine-1-phosphate receptor 1 (S1P1) and diminished migration toward S1P in the PpargC/- splenocytes supports the hindrance of lymphocyte egression as a mechanism for their accumulation. Mechanistically, increased Th17 polarization and IL-17 signaling in the PpargC/- CD4+ T-cells contributed to the B-cell hyper-activation in the spleen. Finally, activation of the remaining PPARγ in PpargC/- mice by pioglitazone increased S1P1 level, decreased Th17 population in the spleen, and ameliorated splenomegaly. Together, our data demonstrate that reduction of Pparg expression in T-helper cells is a critical factor for spontaneous lupus-like autoimmune diseases and define a novel role of PPARγ in lymphocyte trafficking and crosstalk between Th17 and B-cells.
論文目次 Abstract I
Chinese abstract II
Acknowledgement III
Contents IV
Figure list VII
Abbreviations X
Chapter 1. Introduction 1
1.1 Systemic lupus erythematosus (SLE) 1
1.2 Lupus nephritis 1
1.3 Epidemiologic association between SLE and obesity 2
1.4 Peroxisome proliferator-activated receptor gamma (PPARγ) 3
1.5 PPARγ ligands 4
1.6 PPARγ in immunoregulation 5
1.7 PPARγ hypomorphic mice 7
1.8 Sphingosine-1-phosphate receptor 1 8
Chapter 2. Objective and Specific Aims 9
2.1 Objective 9
2.2 Specific aims 9
Chapter 3. Materials and Methods 11
3.1 Mice 11
3.2 Micro-computed tomography (micro-CT) 11
3.3 Flow cytometry 12
3.4 Migration assay 12
3.5 TUNEL assay 13
3.6 Anti-dsDNA ELISA 13
3.7 Detection of anti-nuclear antibodies and immune complex deposition 14
3.8 Scoring of mesangial matrix expansion 14
3.9 BrdU labeling 14
3.10 CFSE labeling 15
3.11 In vitro lymphocyte proliferation and apoptosis assay 15
3.12 In vitro co-culture assay 15
3.13 In vitro CD4+ T-cell differentiation 16
3.14 Western blot analysis 16
3.15 Tissue collection and RNA analysis 17
3.16 Statistical analysis 17
Chapter 4. Results 18
4.1 Spleen enlargement in PPARγ hypomorphic mice 18
4.2 No signs of extramedullary hematopoiesis in the young PpargC/- mice 18
4.3 Reduced S1P1 and migration in the splenocytes of PPARγ hypomorphic mice 19
4.4 Increased proliferation of B-cells and apoptotic cells in vivo in the spleen of PPARγ hypomorphic mice 20
4.5 Increased autoantibody production and development of a lupus-like syndrome in aged PPARγ hypomorphic mice 21
4.6 PPARγ deficiency in effector T-helper cells causes increased B-cell activation 22
4.7 Increased Th17 polarization in PPARγ hypomorphic mice 23
4.8 Enhanced Th17 function promotes B-cell activation through IL-17 signaling in PPARγ hypomorphic mice 24
4.9 Pioglitazone ameliorates splenomegaly in PPARγ hypomorphic mice 24
Chapter 5. Discussion 26
5.1 Phenotype of mice with PPARγ hypomorph 26
5.2 PPARγ regulates lymphocyte trafficking through S1P1 27
5.3 Role of PPARγ in CD4+ T-cells-mediated B-cell activation 28
5.4 Compared the PPARγ hypomorphic mice used in this study with others in autoimmunity 28
5.5 PPARγ regulation in Th17 polarization 29
5.6 Discussion of some discrepancies between our results and previously reported studies 30
5.7 Gene-dosage variation of PPARγ 31
5.8 Clinical studies of PPARγ SNP in autoimmunity 31
Chapter 6. Conclusion 34
References 36
Figures 46
Tables 79
參考文獻 1. Sherer, Y., A. Gorstein, M. J. Fritzler, and Y. Shoenfeld. 2004. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34: 501-537.
2. Tsokos, G. C. 2011. Systemic lupus erythematosus. N Engl J Med 365: 2110-2121.
3. Davidson, A., and C. Aranow. 2010. Lupus nephritis: lessons from murine models. Nat Rev Rheumatol 6: 13-20.
4. Mok, C. C., and C. S. Lau. 2003. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56: 481-490.
5. Lech, M., and H. J. Anders. 2013. The pathogenesis of lupus nephritis. J Am Soc Nephrol 24: 1357-1366.
6. Weening, J. J., V. D. D'Agati, M. M. Schwartz, S. V. Seshan, C. E. Alpers, G. B. Appel, J. E. Balow, J. A. Bruijn, T. Cook, F. Ferrario, A. B. Fogo, E. M. Ginzler, L. Hebert, G. Hill, P. Hill, J. C. Jennette, N. C. Kong, P. Lesavre, M. Lockshin, L. M. Looi, H. Makino, L. A. Moura, and M. Nagata. 2004. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15: 241-250.
7. Moroni, L., I. Bianchi, and A. Lleo. 2012. Geoepidemiology, gender and autoimmune disease. Autoimmun Rev 11: A386-392.
8. Ahima, R. S., and M. A. Lazar. 2013. Physiology. The health risk of obesity--better metrics imperative. Science 341: 856-858.
9. Centers for Disease Control Prevention. 2011. Prevalence of obesity among adults with arthritis --- United States, 2003--2009. MMWR. Morbidity and mortality weekly report 60: 509-513.
10. Owen, K. R., M. Donohoe, S. Ellard, T. J. Clarke, A. J. Nicholls, A. T. Hattersley, and C. Bingham. 2004. Mesangiocapillary glomerulonephritis type 2 associated with
familial partial lipodystrophy (Dunnigan-Kobberling syndrome). Nephron Clin Pract 96: c35-38.
11. Campeau, P. M., O. Astapova, R. Martins, J. Bergeron, P. Couture, R. A. Hegele, T. Leff, and C. Gagne. 2012. Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARgamma deficiency. J Lipid Res 53: 1968-1978.
12. Versini, M., P. Y. Jeandel, E. Rosenthal, and Y. Shoenfeld. 2014. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev 13: 981-1000.
13. Siersbaek, R., R. Nielsen, and S. Mandrup. 2010. PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies. FEBS Lett 584: 3242-3249.
14. Tsai, Y. S., P. J. Tsai, M. J. Jiang, T. Y. Chou, A. Pendse, H. S. Kim, and N. Maeda. 2009. Decreased PPAR gamma expression compromises perigonadal-specific fat deposition and insulin sensitivity. Mol Endocrinol 23: 1787-1798.
15. Greene, M. E., B. Blumberg, O. W. McBride, H. F. Yi, K. Kronquist, K. Kwan, L. Hsieh, G. Greene, and S. D. Nimer. 1995. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr 4: 281-299.
16. Zhu, Y., C. Qi, J. R. Korenberg, X. N. Chen, D. Noya, M. S. Rao, and J. K. Reddy. 1995. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Nati Acad Sci U S A 92: 7921-7925.
17. Fajas, L., D. Auboeuf, E. Raspe, K. Schoonjans, A. M. Lefebvre, R. Saladin, J. Najib, M. Laville, J. C. Fruchart, S. Deeb, A. Vidal-Puig, J. Flier, M. R. Briggs, B. Staels,
H. Vidal, and J. Auwerx. 1997. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 272: 18779-18789.
18. Fajas, L., J. C. Fruchart, and J. Auwerx. 1998. PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett 438: 55-60.
19. Sundvold, H., and S. Lien. 2001. Identification of a novel peroxisome proliferatoractivated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem Biophys Res Commun 287: 383-390.
20. Braissant, O., F. Foufelle, C. Scotto, M. Dauca, and W. Wahli. 1996. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137: 354-366.
21. Rosen, E. D., P. Sarraf, A. E. Troy, G. Bradwin, K. Moore, D. S. Milstone, B. M. Spiegelman, and R. M. Mortensen. 1999. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4: 611-617.
22. Picard, F., and J. Auwerx. 2002. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 22: 167-197.
23. Temple, K. A., R. N. Cohen, S. R. Wondisford, C. Yu, D. Deplewski, and F. E. Wondisford. 2005. An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor gamma (PPARgamma) binding and activation on
some PPAR response elements. J Biol Chem 280: 3529-3540.
24. Nielsen, R., T. A. Pedersen, D. Hagenbeek, P. Moulos, R. Siersbaek, E. Megens, S. Denissov, M. Borgesen, K. J. Francoijs, S. Mandrup, and H. G. Stunnenberg. 2008. Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 22: 2953-2967.
25. Bensinger, S. J., and P. Tontonoz. 2008. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454: 470-477.
26. Choi, J. M., and A. L. Bothwell. 2012. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol Cells 33: 217-222.
27. Yu, S., and J. K. Reddy. 2007. Transcription coactivators for peroxisome proliferatoractivated receptors. Biochim Biophys Acta 1771: 936-951.
28. Zoete, V., A. Grosdidier, and O. Michielin. 2007. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with
regulators. Biochim Biophys Acta 1771: 915-925.
29. Dussault, I., and B. M. Forman. 2000. Prostaglandins and fatty acids regulate transcriptional signaling via the peroxisome proliferator activated receptor nuclear receptors. Prostaglandins Other Lipid Mediat 62: 1-13.
30. Kliewer, S. A., S. S. Sundseth, S. A. Jones, P. J. Brown, G. B. Wisely, C. S. Koble, P. Devchand, W. Wahli, T. M. Willson, J. M. Lenhard, and J. M. Lehmann. 1997. Fatty
acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Nati Acad Sci U S A 94: 4318-4323.
31. Lehmann, J. M., L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer. 1995. An antidiabetic thiazolidinedione is a high affinity ligand
for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270: 12953-12956.
32. Cho, N., and Y. Momose. 2008. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress. Curr Top Med Chem 8: 1483-1507.
33. Scher, J. U., and M. H. Pillinger. 2005. 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol 114: 100-109.
34. Rossi, A., P. Kapahi, G. Natoli, T. Takahashi, Y. Chen, M. Karin, and M. G. Santoro. 2000. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 403: 103-108.
35. Straus, D. S., G. Pascual, M. Li, J. S. Welch, M. Ricote, C. H. Hsiang, L. L. Sengchanthalangsy, G. Ghosh, and C. K. Glass. 2000. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc
Nati Acad Sci U S A 97: 4844-4849.
36. Noble, J., M. O. Baerlocher, and J. Silverberg. 2005. Management of type 2 diabetes mellitus. Role of thiazolidinediones. Can Fam Physician 51: 683-687.
37. Scheen, A. J. 2001. Thiazolidinediones and liver toxicity. Diabetes Metab 27: 305-313.
38. Nissen, S. E., and K. Wolski. 2007. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356: 2457-2471.
39. Forman, L. M., D. A. Simmons, and R. H. Diamond. 2000. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 132: 118-121.
40. Ceriello, A. 2008. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents. Diabetes Metab Res Rev 24: 14-26.
41. Blanquicett, C., J. Roman, and C. M. Hart. 2008. Thiazolidinediones as anti-cancer agents. Cancer Ther 6: 25-34.
42. Panigrahy, D., S. Singer, L. Q. Shen, C. E. Butterfield, D. A. Freedman, E. J. Chen, M. A. Moses, S. Kilroy, S. Duensing, C. Fletcher, J. A. Fletcher, L. Hlatky, P. Hahnfeldt, J. Folkman, and A. Kaipainen. 2002. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 110: 923-932.
43. Kliewer, S. A., B. M. Forman, B. Blumberg, E. S. Ong, U. Borgmeyer, D. J. Mangelsdorf, K. Umesono, and R. M. Evans. 1994. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Nati Acad Sci U S A 91: 7355-7359.
44. Ricote, M., A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass. 1998. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391: 79-82.
45. Jiang, C., A. T. Ting, and B. Seed. 1998. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391: 82-86.
46. Pascual, G., A. L. Fong, S. Ogawa, A. Gamliel, A. C. Li, V. Perissi, D. W. Rose, T. M. Willson, M. G. Rosenfeld, and C. K. Glass. 2005. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.
Nature 437: 759-763.
47. Padilla, J., K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps. 2000. Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. J Immunol 165:6941-6948.
48. Padilla, J., K. Kaur, S. G. Harris, and R. P. Phipps. 2000. PPAR-gamma-mediated regulation of normal and malignant B lineage cells. Ann N Y Acad Sci 905: 97-109.
49. Setoguchi, K., Y. Misaki, Y. Terauchi, T. Yamauchi, K. Kawahata, T. Kadowaki, and K. Yamamoto. 2001. Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B cell proliferative responses and exacerbates
experimentally induced arthritis. J Clin Invest 108: 1667-1675.
50. Ray, D. M., F. Akbiyik, and R. P. Phipps. 2006. The peroxisome proliferatoractivated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms. J Immunol 177: 5068-5076.
51. Ramon, S., S. Bancos, T. H. Thatcher, T. I. Murant, S. Moshkani, J. M. Sahler, A. Bottaro, P. J. Sime, and R. P. Phipps. 2012. Peroxisome proliferator-activated receptor gamma B cell-specific-deficient mice have an impaired antibody response. J Immunol 189: 4740-4747.
52. Harris, S. G., and R. P. Phipps. 2001. The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 31: 1098-1105.
53. Clark, R. B., D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula. 2000. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 164: 1364-1371.
54. Yang, X. Y., L. H. Wang, T. Chen, D. R. Hodge, J. H. Resau, L. DaSilva, and W. L. Farrar. 2000. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma coassociation with transcription factor NFAT. J Biol Chem 275: 4541-4544.
55. Hontecillas, R., and J. Bassaganya-Riera. 2007. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 178: 2940-2949.
56. Guri, A. J., S. K. Mohapatra, W. T. Horne, 2nd, R. Hontecillas, and J. Bassaganya-Riera. 2010. The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease. BMC Gastroenterol 10: 60.
57. Klotz, L., S. Burgdorf, I. Dani, K. Saijo, J. Flossdorf, S. Hucke, J. Alferink, N. Nowak, M. Beyer, G. Mayer, B. Langhans, T. Klockgether, A. Waisman, G. Eberl, J. Schultze, M. Famulok, W. Kolanus, C. Glass, C. Kurts, and P. A. Knolle. 2009. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cellintrinsic fashion and suppresses CNS autoimmunity. J Exp Med 206: 2079-2089.
58. Park, H. J., D. H. Kim, J. Y. Choi, W. J. Kim, J. Y. Kim, A. G. Senejani, S. S. Hwang, L. K. Kim, Z. Tobiasova, G. R. Lee, J. Craft, A. L. Bothwell, and J. M. Choi. 2014.
PPARgamma negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PloS one 9: e99127.
59. Barak, Y., M. C. Nelson, E. S. Ong, Y. Z. Jones, P. Ruiz-Lozano, K. R. Chien, A. Koder, and R. M. Evans. 1999. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol cell 4: 585-595.
60. Miles, P. D., Y. Barak, W. He, R. M. Evans, and J. M. Olefsky. 2000. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 105: 287-292.
61. Tsai, Y. S., A. Pendse, S. S. Moy, I. Mohri, A. Perez, J. N. Crawley, K. Suzuki, and N. Maeda. 2006. A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene. Mamm Genome 17: 716-722.
62. Kluk, M. J., and T. Hla. 2002. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochim Biophys Acta 1582: 72-80.
63. Mandala, S., R. Hajdu, J. Bergstrom, E. Quackenbush, J. Xie, J. Milligan, R. Thornton, G. J. Shei, D. Card, C. Keohane, M. Rosenbach, J. Hale, C. L. Lynch, K. Rupprecht, W. Parsons, and H. Rosen. 2002. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296: 346-349.
64. Matloubian, M., C. G. Lo, G. Cinamon, M. J. Lesneski, Y. Xu, V. Brinkmann, M. L. Allende, R. L. Proia, and J. G. Cyster. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427: 355-360.
65. Allende, M. L., J. L. Dreier, S. Mandala, and R. L. Proia. 2004. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J
Biol Chem 279: 15396-15401.
66. Koch, A., A. Volzke, C. Wunsche, D. Meyer zu Heringdorf, A. Huwiler, and J. Pfeilschifter. 2012. Thiazolidinedione-dependent activation of sphingosine kinase 1 causes an anti-fibrotic effect in renal mesangial cells. Br J Pharmacol 166: 1018-1032.
67. Koch, A., A. Volzke, B. Puff, K. Blankenbach, D. Meyer Zu Heringdorf, A. Huwiler, and J. Pfeilschifter. 2013. PPARgamma agonists upregulate sphingosine 1-phosphate (S1P) receptor 1 expression, which in turn reduces S1P-induced [Ca] increases in renal mesangial cells. Biochim Biophys Acta 1831: 1634-1643.
68. Chen, C. Y., T. M. Chen, and A. B. Shyu. 1994. Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNAdestabilizing function. Mol Cell Biol 14: 416-426.
69. Tsai, Y. S., L. Xu, O. Smithies, and N. Maeda. 2009. Genetic variations in peroxisome proliferator-activated receptor gamma expression affect blood pressure. Proc Nati Acad Sci U S A 106: 19084-19089.
70. Zhang, N., J. Guo, and Y. W. He. 2003. Lymphocyte accumulation in the spleen of retinoic acid receptor-related orphan receptor gamma-deficient mice. J Immunol 171:1667-1675.
71. Stohl, W., D. Xu, K. S. Kim, M. N. Koss, T. N. Jorgensen, B. Deocharan, T. E. Metzger, S. A. Bixler, Y. S. Hong, C. M. Ambrose, F. Mackay, L. Morel, C. Putterman, B. L. Kotzin, and S. L. Kalled. 2005. BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus. Arthritis Rheum 52: 2080-2091.
72. Cock, T. A., J. Back, F. Elefteriou, G. Karsenty, P. Kastner, S. Chan, and J. Auwerx. 2004. Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen. EMBO Rep 5: 1007-1012.
73. Wan, Y., L. W. Chong, and R. M. Evans. 2007. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med 13: 1496-1503.
74. Yan, M., H. Wang, B. Chan, M. Roose-Girma, S. Erickson, T. Baker, D. Tumas, I. S. Grewal, and V. M. Dixit. 2001. Activation and accumulation of B cells in TACIdeficient mice. Nat Immunol 2: 638-643.
75. Garchow, B. G., O. Bartulos Encinas, Y. T. Leung, P. Y. Tsao, R. A. Eisenberg, R. Caricchio, S. Obad, A. Petri, S. Kauppinen, and M. Kiriakidou. 2011. Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med 3: 605-615.
76. Natarajan, C., G. Muthian, Y. Barak, R. M. Evans, and J. J. Bright. 2003. Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic
encephalomyelitis. J Immunol 171: 5743-5750.
77. Roszer, T., M. P. Menendez-Gutierrez, M. I. Lefterova, D. Alameda, V. Nunez, M. A. Lazar, T. Fischer, and M. Ricote. 2011. Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator activated receptor gamma or retinoid X receptor alpha deficiency. J Immunol 186:621-631.
78. Mitsdoerffer, M., Y. Lee, A. Jager, H. J. Kim, T. Korn, J. K. Kolls, H. Cantor, E. Bettelli, and V. K. Kuchroo. 2010. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc Nati Acad Sci U S A 107: 14292-14297.
79. Martin, J. C., D. L. Baeten, and R. Josien. 2014. Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clin Immunol 154: 1-12.
80. Jadidi-Niaragh, F., and A. Mirshafiey. 2011. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74: 1-13.
81. Elloso, M. M., M. Gomez-Angelats, and A. M. Fourie. 2012. Targeting the Th17 pathway in psoriasis. J Leukoc Biol 92: 1187-1197.
82. Leipe, J., M. Grunke, C. Dechant, C. Reindl, U. Kerzendorf, H. Schulze-Koops, and A. Skapenko. 2010. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62: 2876-2885.
83. Galvez, J. 2014. Role of Th17 Cells in the Pathogenesis of Human IBD. ISRN Inflamm 2014: 928461.
84. Ichiyama, K., H. Yoshida, Y. Wakabayashi, T. Chinen, K. Saeki, M. Nakaya, G. Takaesu, S. Hori, A. Yoshimura, and T. Kobayashi. 2008. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 283: 17003-17008.
85. Kim, D. H., H. J. Ihn, C. Moon, S. S. Oh, S. Park, S. Kim, K. W. Lee, and K. D. Kim. 2015. Ciglitazone, a peroxisome proliferator-activated receptor gamma ligand,
inhibits proliferation and differentiation of th17 cells. Biomol Ther (Seoul) 23: 71-76.
86. Schrieber, L., A. D. Steinberg, Y. J. Rosenberg, E. E. Csehi, S. A. Paull, and T. J. Santoro. 1986. Aberrant lymphocyte trafficking in murine systemic lupus erythematosus. Rheumatol Int 6: 215-219.
87. Dorner, T., C. Giesecke, and P. E. Lipsky. 2011. Mechanisms of B cell autoimmunity in SLE. Arthritis Res Ther 13: 243.
88. Shao, W. H., and P. L. Cohen. 2011. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res Ther 13: 202.
89. Carlucci, F., J. Cortes-Hernandez, L. Fossati-Jimack, A. E. Bygrave, M. J. Walport, T. J. Vyse, H. T. Cook, and M. Botto. 2007. Genetic dissection of spontaneous autoimmunity driven by 129-derived chromosome 1 Loci when expressed on
C57BL/6 mice. J Immunol 178: 2352-2360.
90. Heidari, Y., L. Fossati-Jimack, F. Carlucci, M. J. Walport, H. T. Cook, and M. Botto. 2009. A lupus-susceptibility C57BL/6 locus on chromosome 3 (Sle18) contributes to autoantibody production in 129 mice. Genes Immun 10: 47-55.
91. Sato, S., M. Hasegawa, M. Fujimoto, T. F. Tedder, and K. Takehara. 2000. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 165: 6635-6643.
92. Chen, Z., J. Stockton, D. Mathis, and C. Benoist. 2006. Modeling CTLA4-linked autoimmunity with RNA interference in mice. Proc Nati Acad Sci U S A 103: 16400-16405.
93. Deeb, S. S., L. Fajas, M. Nemoto, J. Pihlajamaki, L. Mykkanen, J. Kuusisto, M. Laakso, W. Fujimoto, and J. Auwerx. 1998. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20: 284-287.
94. Butt, C., D. Gladman, and P. Rahman. 2006. PPAR-gamma gene polymorphisms and psoriatic arthritis. J Rheumatol 33: 1631-1633.
95. Jalil, S. F., I. Ahmed, Z. Gauhar, M. Ahmed, J. M. Malik, P. John, and A. Bhatti. 2014. Association of Pro12Ala (rs1801282) variant of PPAR gamma with Rheumatoid Arthritis in a Pakistani population. Rheumatol Int 34: 699-703.
96. Klotz, L., S. Schmidt, R. Heun, T. Klockgether, and H. Kolsch. 2009. Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis. Neurosci Lett 449: 81-83.
97. Pawlak-Adamska, E., J. Daroszewski, M. Bolanowski, J. Oficjalska, P. Janusz, M. Szalinski, and I. Frydecka. 2013. PPARg2 Ala(1)(2) variant protects against Graves' orbitopathy and modulates the course of the disease. Immunogenetics 65: 493-500.
98. Song, J., M. Sakatsume, I. Narita, S. Goto, K. Omori, T. Takada, N. Saito, M. Ueno, and F. Gejyo. 2003. Peroxisome proliferator-activated receptor gamma C161T polymorphisms and survival of Japanese patients with immunoglobulin A nephropathy. Clin Genet 64: 398-403.
99. Zhao, W., C. C. Berthier, E. E. Lewis, W. J. McCune, M. Kretzler, and M. J. Kaplan. 2013. The peroxisome-proliferator activated receptor-gamma agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus. Clin Immunol 149: 119-132.
100. Okunuki, Y., Y. Usui, H. Nakagawa, K. Tajima, R. Matsuda, S. Ueda, T. Hattori, T. Kezuka, and H. Goto. 2013. Peroxisome proliferator-activated receptor-gamma agonist pioglitazone suppresses experimental autoimmune uveitis. Exp Eye Res 116:291-297.
101. Pershadsingh, H. A., M. T. Heneka, R. Saini, N. M. Amin, D. J. Broeske, and D. L. Feinstein. 2004. Effect of pioglitazone treatment in a patient with secondary multiple
sclerosis. J Neuroinflammation 1: 3.
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