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PPAR Research
Volume 2008 (2008), Article ID 895901, 12 pages
http://dx.doi.org/10.1155/2008/895901
Review Article

Regulation of Lymphocyte Function by PPAR 𝛾 : Relevance to Thyroid Eye Disease-Related Inflammation

1Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA
2Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA
3Division of Molecular Medicine, Harbor-UCLA Medical Center, California Los Angeles Medical Center, Torrance, CA 90502, USA
4Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA 90095, USA
5David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
6University of Rochester Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
7Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA

Received 29 October 2007; Accepted 12 December 2007

Academic Editor: Suofu Qin

Copyright © 2008 G. M. Lehmann et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. K. Glass and S. Ogawa, “Combinatorial roles of nuclear receptors in inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 1, pp. 44–55, 2006. View at Publisher · View at Google Scholar
  2. H. Duez, J.-C. Fruchart, and B. Staels, “PPARs in inflammation, atherosclerosis and thrombosis,” Journal of Cardiovascular Risk, vol. 8, no. 4, pp. 187–194, 2001. View at Publisher · View at Google Scholar
  3. D. M. Ray, S. L. Spinelli, J. J. O'Brien, N. Blumberg, and R. P. Phipps, “Platelets as a novel target for PPARγ ligands: implications for inflammation, diabetes, and cardiovascular disease,” BioDrugs, vol. 20, no. 4, pp. 231–241, 2006. View at Publisher · View at Google Scholar
  4. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at Publisher · View at Google Scholar
  5. S. G. Harris and R. P. Phipps, “The nuclear receptor PPAR γ is expressed by mouse T lymphocytes and PPAR γ agonists induce apoptosis,” European Journal of Immunology, vol. 31, no. 4, pp. 1098–1105, 2001. View at Publisher · View at Google Scholar
  6. D. M. Ray, S. H. Bernstein, and R. P. Phipps, “Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands,” Clinical Immunology, vol. 113, no. 2, pp. 203–213, 2004. View at Publisher · View at Google Scholar
  7. D. C. Jones, X. Ding, and R. A. Daynes, “Nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is expressed in resting murine lymphocytes. The PPARα in T and B lymphocytes is both transactivation and transrepression competent,” Journal of Biological Chemistry, vol. 277, no. 9, pp. 6838–6845, 2002. View at Publisher · View at Google Scholar
  8. D. Pasquali, G. M. Pierantoni, A. Fusco et al., “Fenofibrate increases the expression of high mobility group AT-hook 2 (HMGA2) gene and induces adipocyte differentiation of orbital fibroblasts from Graves' ophthalmopathy,” Journal of Molecular Endocrinology, vol. 33, no. 1, pp. 133–143, 2004. View at Publisher · View at Google Scholar
  9. D. Auboeuf, J. Rieusset, L. Fajas et al., “Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-a in humans: no alteration in adipose tissue of obese and NIDDM patients,” Diabetes, vol. 46, no. 8, pp. 1319–1327, 1997. View at Publisher · View at Google Scholar
  10. N. Marx, H. Duez, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells,” Circulation Research, vol. 94, no. 9, pp. 1168–1178, 2004. View at Publisher · View at Google Scholar
  11. J. Plutzky, “Inflammation in atherosclerosis and diabetes mellitus,” Reviews in Endocrine & Metabolic Disorders, vol. 5, no. 3, pp. 255–259, 2004. View at Publisher · View at Google Scholar
  12. J. Auwerx, K. Schoonjans, J.-C. Fruchart, and B. Staels, “Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR,” Atherosclerosis, vol. 124, 1, pp. S29–S37, 1996. View at Publisher · View at Google Scholar
  13. J. D. Brown and J. Plutzky, “Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets,” Circulation, vol. 115, no. 4, pp. 518–533, 2007. View at Publisher · View at Google Scholar
  14. X. Zhou, K. F. Benson, H. R. Ashar, and K. Chada, “Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C,” Nature, vol. 376, no. 6543, pp. 771–774, 1995. View at Publisher · View at Google Scholar
  15. S. Battista, V. Fidanza, M. Fedele et al., “The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis,” Cancer Research, vol. 59, no. 19, pp. 4793–4797, 1999. View at Google Scholar
  16. A. Anand and K. Chada, “In vivo modulation of Hmgic reduces obesity,” Nature Genetics, vol. 24, no. 4, pp. 377–380, 2000. View at Publisher · View at Google Scholar
  17. P. Arlotta, A. K.-F. Tai, G. Manfioletti, C. Clifford, G. Jay, and S. J. Ono, “Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas,” Journal of Biological Chemistry, vol. 275, no. 19, pp. 14394–14400, 2000. View at Publisher · View at Google Scholar
  18. R. Brandes, R. Arad, and J. Bar-Tana, “Adipose conversion of cultured rat primary preadipocytes by hypolipidemic drugs,” Biochimica et Biophysica Acta, vol. 877, no. 2, pp. 314–321, 1986. View at Publisher · View at Google Scholar
  19. A. Nencioni, F. Grünebach, A. Zobywlaski, C. Denzlinger, W. Brugger, and P. Brossart, “Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor γ,” Journal of Immunology, vol. 169, no. 3, pp. 1228–1235, 2002. View at Google Scholar
  20. F. Akbiyik, D. M. Ray, K. F. Gettings, N. Blumberg, C. W. Francis, and R. P. Phipps, “Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes,” Blood, vol. 104, no. 5, pp. 1361–1368, 2004. View at Publisher · View at Google Scholar
  21. K. Setoguchi, Y. Misaki, Y. Terauchi et al., “Peroxisome proliferator-activated receptor-? haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis,” Journal of Clinical Investigation, vol. 108, no. 11, pp. 1667–1675, 2001. View at Publisher · View at Google Scholar
  22. R. Cunard, M. Ricote, D. DiCampli et al., “Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors,” Journal of Immunology, vol. 168, no. 6, pp. 2795–2802, 2002. View at Google Scholar
  23. R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula, “The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses,” Journal of Immunology, vol. 164, no. 3, pp. 1364–1371, 2000. View at Google Scholar
  24. J. Padilla, E. Leung, and R. P. Phipps, “Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists,” Clinical Immunology, vol. 103, no. 1, pp. 22–33, 2002. View at Publisher · View at Google Scholar
  25. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar
  26. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPAR? gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar
  27. M. Ricote, J. Huang, L. Fajas et al., “Expression of the peroxisome proliferator-activated receptor ? (PPAR?) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7614–7619, 1998. View at Publisher · View at Google Scholar
  28. S. E. Feldon, C. W. O'Loughlin, D. M. Ray, S. Landskroner-Eiger, K. E. Seweryniak, and R. P. Phipps, “Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes,” The American Journal of Pathology, vol. 169, no. 4, pp. 1183–1193, 2006. View at Publisher · View at Google Scholar
  29. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  30. T. M. McIntyre, A. V. Pontsler, A. R. Silva et al., “Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR? agonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 131–136, 2003. View at Publisher · View at Google Scholar
  31. F. J. Schopfer, Y. Lin, P. R. S. Baker et al., “Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor ? ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2340–2345, 2005. View at Publisher · View at Google Scholar
  32. B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ,” Cell, vol. 83, no. 5, pp. 803–812, 1995. View at Publisher · View at Google Scholar
  33. S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995. View at Publisher · View at Google Scholar
  34. S. Kumar, M. J. Coenen, P. E. Scherer, and R. S. Bahn, “Evidence for enhanced adipogenesis in the orbits of patients with Graves' ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 2, pp. 930–935, 2004. View at Publisher · View at Google Scholar
  35. A. Antonelli, M. Rotondi, S. M. Ferrari et al., “Interferon-?-inducible a-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-? agonists,” Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 2, pp. 614–620, 2006. View at Publisher · View at Google Scholar
  36. K. Starkey, A. E. Heufelder, G. Baker et al., “Peroxisome proliferator-activated receptor-? in thyroid eye disease: contraindication for thiazolidinedione use?” Journal of Clinical Endocrinology & Metabolism, vol. 88, no. 1, pp. 55–59, 2003. View at Publisher · View at Google Scholar
  37. T. J. Smith, L. Koumas, A. Gagnon et al., “Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 87, no. 1, pp. 385–392, 2002. View at Publisher · View at Google Scholar
  38. M. Söderström, J. Wigren, S. Surapureddi, C. K. Glass, and S. Hammarström, “Novel prostaglandin D2-derived activators of peroxisome proliferator-activated receptor-γ are formed in macrophage cell cultures,” Biochimica et Biophysica Acta, vol. 1631, no. 1, pp. 35–41, 2003. View at Publisher · View at Google Scholar
  39. J. Kim, P. Yang, M. Suraokar et al., “Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products,” Cancer Research, vol. 65, no. 14, pp. 6189–6198, 2005. View at Publisher · View at Google Scholar
  40. M. Fukushima, “Biological activities and mechanisms of action of PGJ2 and related compounds: an update,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 47, no. 1, pp. 1–12, 1992. View at Publisher · View at Google Scholar
  41. F. A. Fitzpatrick and M. A. Wynalda, “Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro,” Journal of Biological Chemistry, vol. 258, no. 19, pp. 11713–11718, 1983. View at Google Scholar
  42. P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994. View at Publisher · View at Google Scholar
  43. N. Kubota, Y. Terauchi, H. Miki et al., “PPAR? mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance,” Molecular Cell, vol. 4, no. 4, pp. 597–609, 1999. View at Publisher · View at Google Scholar
  44. E. D. Rosen, P. Sarraf, A. E. Troy et al., “PPAR? is required for the differentiation of adipose tissue in vivo and in vitro,” Molecular Cell, vol. 4, no. 4, pp. 611–617, 1999. View at Publisher · View at Google Scholar
  45. P. Delerive, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors in inflammation control,” Journal of Endocrinology, vol. 169, no. 3, pp. 453–459, 2001. View at Publisher · View at Google Scholar
  46. M. Kazim, R. A. Goldberg, and T. J. Smith, “Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy,” Archives of Ophthalmology, vol. 120, no. 3, pp. 380–386, 2002. View at Google Scholar
  47. R. Han and T. J. Smith, “T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1β in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy,” Endocrinology, vol. 147, no. 1, pp. 13–19, 2006. View at Publisher · View at Google Scholar
  48. T. J. Smith and N. Hoa, “Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor,” Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 10, pp. 5076–5080, 2004. View at Publisher · View at Google Scholar
  49. T. J. Smith, R. S. Bahn, and C. A. Gorman, “Connective tissue, glycosaminoglycans, and diseases of the thyroid,” Endocrine Reviews, vol. 10, no. 3, pp. 366–391, 1989. View at Publisher · View at Google Scholar
  50. S. E. Feldon, D. J. John Park, C. W. O'Loughlin et al., “Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy,” Investigative Ophthalmology & Visual Science, vol. 46, no. 11, pp. 3913–3921, 2005. View at Publisher · View at Google Scholar
  51. G. Kahaly, G. Förster, and C. Hansen, “Glycosaminoglycans in thyroid eye disease,” Thyroid, vol. 8, no. 5, pp. 429–432, 1998. View at Publisher · View at Google Scholar
  52. L. Tallstedt and R. Norberg, “Immunohistochemical staining of normal and Graves' extraocular muscle,” Investigative Ophthalmology & Visual Science, vol. 29, no. 2, pp. 175–184, 1988. View at Google Scholar
  53. S. L. Trokel and F. A. Jakobiec, “Correlation of CT scanning and pathologic features of ophthalmic Graves' disease,” Ophthalmology, vol. 88, no. 6, pp. 553–564, 1981. View at Google Scholar
  54. L. Zhang, G. Baker, D. Janus, C. A. Paddon, D. Fuhrer, and M. Ludgate, “Biological effects of thyrotropin receptor activation on human orbital preadipocytes,” Investigative Ophthalmology & Visual Science, vol. 47, no. 12, pp. 5197–5203, 2006. View at Publisher · View at Google Scholar
  55. M. Ludgate and G. Baker, “Unlocking the immunological mechanisms of orbital inflammation in thyroid eye disease,” Clinical & Experimental Immunology, vol. 127, no. 2, pp. 193–198, 2002. View at Publisher · View at Google Scholar
  56. M. P. Hatton and P. A. Rubin, “The pathophysiology of thyroid-associated ophthalmopathy,” Ophthalmology Clinics of North America, vol. 15, no. 1, pp. 113–119, 2002. View at Publisher · View at Google Scholar
  57. R. S. Bahn and A. E. Heufelder, “Pathogenesis of Graves' ophthalmopathy,” The New England Journal of Medicine, vol. 329, no. 20, pp. 1468–1475, 1993. View at Publisher · View at Google Scholar
  58. B. S. Prabhakar, R. S. Bahn, and T. J. Smith, “Current perspective on the pathogenesis of Graves' disease and ophthalmopathy,” Endocrine Reviews, vol. 24, no. 6, pp. 802–835, 2003. View at Publisher · View at Google Scholar
  59. R. S. Douglas, A. G. Gianoukakis, R. A. Goldberg, S. Kamat, and T. J. Smith, “Circulating mononuclear cells from euthyroid patients with thyroid-associated ophthalmopathy exhibit characteristic phenotypes,” Clinical & Experimental Immunology, vol. 148, no. 1, pp. 64–71, 2007. View at Google Scholar
  60. B. Rapoport, R. Alsabeh, D. Aftergood, and S. M. McLachlan, “Elephantiasic pretibial myxedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves' disease,” Thyroid, vol. 10, no. 8, pp. 685–692, 2000. View at Publisher · View at Google Scholar
  61. C. Daumerie, M. Ludgate, S. Costagliola, and M. C. Many, “Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy,” European Journal of Endocrinology, vol. 146, no. 1, pp. 35–38, 2002. View at Publisher · View at Google Scholar
  62. J. M. Kim, L. LaBree, L. Levin, and S. E. Feldon, “The relation of Graves' ophthalmopathy to circulating thyroid hormone status,” British Journal of Ophthalmology, vol. 88, no. 1, pp. 72–74, 2004. View at Publisher · View at Google Scholar
  63. H. B. Burch and L. Wartofsky, “Graves' ophthalmopathy: current concepts regarding pathogenesis and management,” Endocrine Reviews, vol. 14, no. 6, pp. 747–793, 1993. View at Publisher · View at Google Scholar
  64. J. R. Reid and S. F. Wheeler, “Hyperthyroidism: diagnosis and treatment,” American Family Physician, vol. 72, no. 4, pp. 623–630, 2005. View at Google Scholar
  65. L. Bartalena, W. M. Wiersinga, and A. Pinchera, “Graves' ophthalmopathy: state of the art and perspectives,” Journal of Endocrinological Investigation, vol. 27, no. 3, pp. 295–301, 2004. View at Google Scholar
  66. T. J. Smith, “Insights into the role of fibroblasts in human autoimmune diseases,” Clinical & Experimental Immunology, vol. 141, no. 3, pp. 388–397, 2005. View at Publisher · View at Google Scholar
  67. D. H. Khoo, S. C. Ho, L. L. Seah et al., “The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy,” Thyroid, vol. 9, no. 12, pp. 1175–1180, 1999. View at Publisher · View at Google Scholar
  68. R. Wright-Pascoe, M. F. Smikle, E. N. Barton, and O. B. James, “Limited usefulness of antithyroperoxidase and antithyroglobulin assays in Jamaicans with Graves' disease,” Human Antibodies, vol. 9, no. 3, pp. 161–164, 1999. View at Google Scholar
  69. A. K. Eckstein, M. Plicht, H. Lax et al., “Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies,” Clinical Endocrinology, vol. 61, no. 5, pp. 612–618, 2004. View at Publisher · View at Google Scholar
  70. D. Liu and S. E. Feldon, “Thyroid ophthalmopathy,” Ophthalmology Clinics of North America, vol. 5, pp. 597–622, 1992. View at Google Scholar
  71. G. M. Lehmann, S. E. Feldon, T. J. Smith, and R. P. Phipps, “Immune mechanisms in thyroid eye disease,” Thyroid. In pres.
  72. R. S. Smith, T. J. Smith, T. M. Blieden, and R. P. Phipps, “Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation,” The American Journal of Pathology, vol. 151, no. 2, pp. 317–322, 1997. View at Google Scholar
  73. L. Koumas, T. J. Smith, and R. P. Phipps, “Fibroblast subsets in the human orbit: Thy-1+ and Thy-1- subpopulations exhibit distinct phenotypes,” European Journal of Immunology, vol. 32, no. 2, pp. 477–485, 2002. View at Publisher · View at Google Scholar
  74. G. D. Sempowski, J. Rozenblit, T. J. Smith, and R. P. Phipps, “Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production,” American Journal of Physiology, vol. 274, no. 3, pp. C707–C714, 1998. View at Google Scholar
  75. T. J. Smith, “Orbital fibroblasts exhibit a novel pattern of responses to proinflammatory cytokines: potential basis for the pathogenesis of thyroid-associated ophthalmopathy,” Thyroid, vol. 12, no. 3, pp. 197–203, 2002. View at Publisher · View at Google Scholar
  76. A. E. Heufelder, T. J. Smith, C. A. Gorman, and R. S. Bahn, “Increased induction of HLA-DR by interferon-γ in cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial dermopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 73, no. 2, pp. 307–313, 1991. View at Google Scholar
  77. T. J. Smith, G. D. Sempowski, C. S. Berenson, H. J. Cao, H.-S. Wang, and R. P. Phipps, “Human thyroid fibroblasts exhibit a distinctive phenotype in culture: characteristic ganglioside profile and functional CD40 expression,” Endocrinology, vol. 138, no. 12, pp. 5576–5588, 1997. View at Publisher · View at Google Scholar
  78. T. J. Hufnagel, W. F. Hickey, W. H. Cobbs, F. A. Jakobiec, T. Iwamoto, and R. C. Eagle, “Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease,” Ophthalmology, vol. 91, no. 11, pp. 1411–1419, 1984. View at Google Scholar
  79. M. de Carli, M. M. D'Elios, S. Mariotti et al., “Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 77, no. 5, pp. 1120–1124, 1993. View at Publisher · View at Google Scholar
  80. B. Grubeck-Loebenstein, K. Trieb, A. Sztankay, W. Holter, H. Anderl, and G. Wick, “Retrobulbar T cells from patients with Graves' ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts,” Journal of Clinical Investigation, vol. 93, no. 6, pp. 2738–2743, 1994. View at Publisher · View at Google Scholar
  81. J. C. Jaume, S. Portolano, M. F. Prummel, S. M. McLachlan, and B. Rapoport, “Molecular cloning and characterization of genes for antibodies generated by orbital tissue-infiltrating B-cells in Graves' ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 78, no. 2, pp. 348–352, 1994. View at Publisher · View at Google Scholar
  82. J. P. Aniszewski, R. W. Valyasevi, and R. S. Bahn, “Relationship between disease duration and predominant orbital T cell subset in Graves' ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 85, no. 2, pp. 776–780, 2000. View at Publisher · View at Google Scholar
  83. J. D. Powell, “The induction and maintenance of T cell anergy,” Clinical Immunology, vol. 120, no. 3, pp. 239–246, 2006. View at Publisher · View at Google Scholar
  84. F. Melchers, “Anergic B cells caught in the act,” Immunity, vol. 25, no. 6, pp. 864–867, 2006. View at Publisher · View at Google Scholar
  85. T. J. Smith, “B cell depletion in Graves' disease: the right answer to the wrong question?” Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 5, pp. 1620–1622, 2007. View at Publisher · View at Google Scholar
  86. H. J. Cao, H.-S. Wang, Y. Zhang, H.-Y. Lin, R. P. Phipps, and T. J. Smith, “Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression: insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy,” Journal of Biological Chemistry, vol. 273, no. 45, pp. 29615–29625, 1998. View at Publisher · View at Google Scholar
  87. R. W. Valyasevi, D. Z. Erickson, D. A. Harteneck et al., “Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor,” Journal of Clinical Endocrinology & Metabolism, vol. 84, no. 7, pp. 2257–2562, 1999. View at Publisher · View at Google Scholar
  88. T. J. Smith, D. Sciaky, R. P. Phipps, and T. A. Jennings, “CD40 expression in human thyroid tissue: evidence for involvement of multiple cell types in autoimmune and neoplastic diseases,” Thyroid, vol. 9, no. 8, pp. 749–755, 1999. View at Publisher · View at Google Scholar
  89. H. J. Cao, R. Han, and T. J. Smith, “Robust induction of PGHS-2 by IL-1 in orbital fibroblasts results from low levels of IL-1 receptor antagonist expression,” American Journal of Physiology, vol. 284, no. 6, pp. C1429–C1437, 2003. View at Google Scholar
  90. T. J. Smith, T. A. Jennings, D. Sciaky, and H. J. Cao, “Prostaglandin-endoperoxide H synthase-2 expression in human thyroid epithelium: evidence for constitutive expression in vivo and in cultured KAT- 50 cells,” Journal of Biological Chemistry, vol. 274, no. 22, pp. 15622–15632, 1999. View at Publisher · View at Google Scholar
  91. T. J. Smith, “The putative role of prostaglandin endoperoxide H synthase-2 in the pathogenesis of thyroid-associated orbitopathy,” Experimental and Clinical Endocrinology and Diabetes, vol. 107, 5, pp. S160–S163, 1999. View at Google Scholar
  92. T. J. Smith, “The putative role of fibroblasts in the pathogenesis of Graves' disease: evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation,” Autoimmunity, vol. 36, no. 6-7, pp. 409–415, 2003. View at Publisher · View at Google Scholar
  93. T. J. Smith and S. J. Parikh, “HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis,” Endocrinology, vol. 140, no. 8, pp. 3518–3525, 1999. View at Publisher · View at Google Scholar
  94. T. J. Smith, “Unique properties of orbital connective tissue underlie its involvement in Graves' disease,” Minerva Endocrinologica, vol. 28, no. 3, pp. 213–222, 2003. View at Google Scholar
  95. R. S. Bahn, C. M. Dutton, N. Natt, W. Joba, C. Spitzweg, and A. E. Heufelder, “Thyrotropin receptor expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' ophthalmopathy,” Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 3, pp. 998–1002, 1998. View at Publisher · View at Google Scholar
  96. J. Pritchard, R. Han, N. Horst, W. W. Cruikshank, and T. J. Smith, “Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway,” Journal of Immunology, vol. 170, no. 12, pp. 6348–6354, 2003. View at Google Scholar
  97. A. Feliciello, A. Porcellini, I. Ciullo, G. Bonavolonta, E. V. Avvedimento, and G. F. Fenzi, “Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue,” The Lancet, vol. 342, no. 8867, pp. 337–338, 1993. View at Publisher · View at Google Scholar
  98. M. S. Crisp, C. Lane, M. Halliwell, D. Wynford-Thomas, and M. Ludgate, “Thyrotropin receptor transcripts in human adipose tissue,” Journal of Clinical Endocrinology & Metabolism, vol. 82, no. 6, pp. 2003–2005, 1997. View at Google Scholar
  99. A. E. Heufelder and R. S. Bahn, “Detection and localization of cytokine immunoreactivity in retro-ocular connective tissue in Graves' ophthalmopathy,” European Journal of Clinical Investigation, vol. 23, no. 1, pp. 10–17, 1993. View at Publisher · View at Google Scholar
  100. K. C. Howland, L. J. Ausubel, C. A. London, and A. K. Abbas, “The roles of CD28 and CD40 ligand in T cell activation and tolerance,” Journal of Immunology, vol. 164, no. 9, pp. 4465–4470, 2000. View at Google Scholar
  101. S. W. Van Gool, P. Vandenberghe, M. de Boer, and J. L. Ceuppens, “CD80, CD86 and CD40 provide accessory signals in a multiple-step T-Cell activation model,” Immunological Reviews, no. 153, pp. 47–83, 1996. View at Publisher · View at Google Scholar
  102. Y. Zhang, H. J. Cao, B. Graf, H. Meekins, T. J. Smith, and R. P. Phipps, “Cutting edge: CD40 engagement up-regulates cyclooxygenase-2 expression and prostaglandin E2 production in human lung fibroblasts,” Journal of Immunology, vol. 160, no. 3, pp. 1053–1057, 1998. View at Google Scholar
  103. E. A. Otto, K. Ochs, C. Hansen, J. R. Wall, and G. J. Kahaly, “Orbital tissue-derived T lymphocytes from patients with Graves’ ophthalmopathy recognize autologous orbital antigens,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 8, pp. 3045–3050, 1996. View at Publisher · View at Google Scholar
  104. P. Desreumaux, L. Dubuquoy, S. Nutten et al., “Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor ? (PPAR?) heterodimer: a basis for new therapeutic strategies,” Journal of Experimental Medicine, vol. 193, no. 7, pp. 827–838, 2001. View at Publisher · View at Google Scholar
  105. C. G. Su, X. Wen, S. T. Bailey et al., “A novel therapy for colitis utilizing PPAR-? ligands to inhibit the epithelial inflammatory response,” Journal of Clinical Investigation, vol. 104, no. 4, pp. 383–389, 1999. View at Publisher · View at Google Scholar
  106. K. L. Schaefer, S. Denevich, C. Ma et al., “Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-? ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms,” Inflammatory Bowel Diseases, vol. 11, no. 3, pp. 244–252, 2005. View at Publisher · View at Google Scholar
  107. D. L. Feinstein, E. Galea, V. Gavrilyuk et al., “Peroxisome proliferator-activated receptor-? agonists prevent experimental autoimmune encephalomyelitis,” Annals of Neurology, vol. 51, no. 6, pp. 694–702, 2002. View at Publisher · View at Google Scholar
  108. A. Diab, C. Deng, J. D. Smith et al., “Peroxisome proliferator-activated receptor-? agonist 15-deoxy-?12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 168, no. 5, pp. 2508–2515, 2002. View at Google Scholar
  109. C. N. Ellis, J. Varani, G. J. Fisher et al., “Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-? inhibit keratinocyte proliferation,” Archives of Dermatology, vol. 136, no. 5, pp. 609–616, 2000. View at Publisher · View at Google Scholar
  110. J. D. Lewis, G. R. Lichtenstein, R. B. Stein et al., “An open-label trial of the PPAR? ligand rosiglitazone for active ulcerative colitis,” The American Journal of Gastroenterology, vol. 96, no. 12, pp. 3323–3328, 2001. View at Publisher · View at Google Scholar
  111. A. Kornbluth, “What happened to drug trials in ulcerative colitis? Problems, PPARs, placebos, and (possible) progress,” American Journal of Gastroenterology, vol. 96, no. 12, pp. 3232–3234, 2001. View at Publisher · View at Google Scholar
  112. R. B. Clark, “The role of PPARs in inflammation and immunity,” Journal of Leukocyte Biology, vol. 71, no. 3, pp. 388–400, 2002. View at Google Scholar
  113. D. M. Ray, F. Akbiyik, S. H. Bernstein, and R. P. Phipps, “CD40 engagement prevents peroxisome proliferator-activated receptor γ agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-κB-dependent mechanism,” Journal of Immunology, vol. 174, no. 7, pp. 4060–4069, 2005. View at Google Scholar
  114. D. M. Ray, F. Akbiyik, and R. P. Phipps, “The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxyΔ12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms,” Journal of Immunology, vol. 177, no. 8, pp. 5068–5076, 2006. View at Google Scholar
  115. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998. View at Publisher · View at Google Scholar
  116. M. Ricote, J. S. Welch, and C. K. Glass, “Regulation of macrophage gene expression by the peroxisome proliferator-activated receptor-γ,” Hormone Research, vol. 54, no. 5-6, pp. 275–280, 2000. View at Publisher · View at Google Scholar
  117. M. A. Bouhlel, B. Derudas, E. Rigamonti et al., “PPAR? activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties,” Cell Metabolism, vol. 6, no. 2, pp. 137–143, 2007. View at Publisher · View at Google Scholar
  118. P. Gosset, A.-S. Charbonnier, P. Delerive et al., “Peroxisome proliferator-activated receptor ? activators affect the maturation of human monocyte-derived dendritic cells,” European Journal of Immunology, vol. 31, no. 10, pp. 2857–2865, 2001. View at Publisher · View at Google Scholar
  119. J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps, “Peroxisome proliferator activator receptor-γ agonists and 15-deoxy-Δ12,14-PGJ2 induce apoptosis in normal and malignant B-lineage cells,” Journal of Immunology, vol. 165, no. 12, pp. 6941–6948, 2000. View at Google Scholar
  120. F. Chen, M. Wang, J. P. O'Connor, M. He, T. Tripathi, and L. E. Harrison, “Phosphorylation of PPARγ via active ERK1/2 leads to its physical association with p65 and inhibition of NF-κβ,” Journal of Cellular Biochemistry, vol. 90, no. 4, pp. 732–744, 2003. View at Publisher · View at Google Scholar
  121. J. S. Welch, M. Ricote, T. E. Akiyama, F. J. Gonzalez, and C. K. Glass, “PPARγ and PPARδ negatively regulate specific subsets of lipopolysaccharide and IFN-γ target genes in macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 11, pp. 6712–6717, 2003. View at Publisher · View at Google Scholar
  122. A. Chawla, Y. Barak, L. Nagy, D. Liao, P. Tontonoz, and R. M. Evans, “PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation,” Nature Medicine, vol. 7, no. 1, pp. 48–52, 2001. View at Publisher · View at Google Scholar
  123. R. A. Daynes and D. C. Jones, “Emerging roles of PPARs in inflammation and immunity,” Nature Reviews Immunology, vol. 2, no. 10, pp. 748–759, 2002. View at Publisher · View at Google Scholar
  124. G. Pascual, A. L. Fong, S. Ogawa et al., “A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-?,” Nature, vol. 437, no. 7059, pp. 759–763, 2005. View at Publisher · View at Google Scholar
  125. S. G. Harris and R. P. Phipps, “Peroxisome proliferator-activated receptor γ (PPAR-γ) activation in naive mouse T cells induces cell death,” Annals of the New York Academy of Sciences, vol. 905, pp. 297–300, 2000. View at Google Scholar
  126. H. J. Kim, Y. H. Rho, S. J. Choi et al., “15-deoxy-?12,14-PGJ2 inhibits IL-6-induced Stat3 phosphorylation in lymphocytes,” Experimental and Molecular Medicine, vol. 37, no. 3, pp. 179–185, 2005. View at Google Scholar
  127. M. Soller, A. Tautenhahn, B. Brüne et al., “Peroxisome proliferator-activated receptor ? contributes to T lymphocyte apoptosis during sepsis,” Journal of Leukocyte Biology, vol. 79, no. 1, pp. 235–243, 2006. View at Publisher · View at Google Scholar
  128. X. Y. Yang, L. H. Wang, T. Chen et al., “Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor ? (PPAR?) agonists. PPAR? co-association with transcription factor NFAT,” Journal of Biological Chemistry, vol. 275, no. 7, pp. 4541–4544, 2000. View at Publisher · View at Google Scholar
  129. E. A. Wohlfert, F. C. Nichols, E. Nevius, and R. B. Clark, “Peroxisome proliferator-activated receptor γ (PPARγ) and immunoregulation: enhancement of regulatory T cells through PPARγ-dependent and -independent mechanisms,” Journal of Immunology, vol. 178, no. 7, pp. 4129–4135, 2007. View at Google Scholar
  130. S. Onizuka, I. Tawara, J. Shimizu, S. Sakaguchi, T. Fujita, and E. Nakayama, “Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody,” Cancer Research, vol. 59, no. 13, pp. 3128–3133, 1999. View at Google Scholar
  131. M. Edinger, P. Hoffmann, J. Ermann et al., “CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation,” Nature Medicine, vol. 9, no. 9, pp. 1144–1150, 2003. View at Publisher · View at Google Scholar
  132. S. Paust and H. Cantor, “Regulatory T cells and autoimmune disease,” Immunological Reviews, vol. 204, no. 1, pp. 195–207, 2005. View at Publisher · View at Google Scholar
  133. J. A. Bluestone and A. K. Abbas, “Natural versus adaptive regulatory T cells,” Nature Reviews Immunology, vol. 3, no. 3, pp. 253–257, 2003. View at Publisher · View at Google Scholar
  134. W. Chen, W. Jin, N. Hardegen et al., “Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-ß induction of transcription factor Foxp3,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1875–1886, 2003. View at Publisher · View at Google Scholar
  135. L. Y. Mimura, S. M. F. Villares, M. L. R. Monteiro, I. C. Guazzelli, and W. Bloise, “Peroxisome proliferator-activated receptor-γ gene expression in orbital adipose/connective tissues is increased during the active stage of Graves’ ophthalmopathy,” Thyroid, vol. 13, no. 9, pp. 845–850, 2003. View at Publisher · View at Google Scholar
  136. N. Marx, F. Mach, A. Sauty et al., “Peroxisome proliferator-activated receptor-? activators inhibit IFN-?-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells,” Journal of Immunology, vol. 164, pp. 6503–6508, 2000. View at Google Scholar
  137. S. G. Harris and R. P. Phipps, “Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-γ agonists induce apoptosis in transformed, but not normal, human T lineage cells,” Immunology, vol. 105, no. 1, pp. 23–34, 2002. View at Publisher · View at Google Scholar
  138. S. G. Harris, R. S. Smith, and R. P. Phipps, “15-deoxy-Δ12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway,” Journal of Immunology, vol. 168, no. 3, pp. 1372–1379, 2002. View at Google Scholar
  139. J. Zhang, M. Fu, T. Cui et al., “Selective disruption of PPAR?2 impairs the development of adipose tissue and insulin sensitivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10703–10708, 2004. View at Publisher · View at Google Scholar
  140. E. D. Rosen, “The transcriptional basis of adipocyte development,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 73, no. 1, pp. 31–34, 2005. View at Publisher · View at Google Scholar
  141. T. Shibata, M. Kondo, T. Osawa, N. Shibata, M. Kobayashi, and K. Uchida, “15-deoxy-Δ12,14-prostaglandin J2. A prostaglandin D2 metabolite generated during inflammatory processes,” Journal of Biological Chemistry, vol. 277, no. 12, pp. 10459–10466, 2002. View at Publisher · View at Google Scholar
  142. G. Kahaly, C. Hansen, B. Felke, and H. P. Dienes, “Immunohistochemical staining of retrobulbar adipose tissue in Graves’ ophthalmopathy,” Clinical Immunology and Immunopathology, vol. 73, no. 1, pp. 53–62, 1994. View at Publisher · View at Google Scholar
  143. F. Levin, M. Kazim, T. J. Smith, and E. Marcovici, “Rosiglitazone-induced proptosis,” Archives of Ophthalmology, vol. 123, no. 1, pp. 119–121, 2005. View at Publisher · View at Google Scholar
  144. F. Zhang, B. E. Lavan, and F. M. Gregoire, “Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects,” PPAR Research, vol. 2007, Article ID 32696, 7 pages, 2007. View at Publisher · View at Google Scholar
  145. S. M. Rangwala and M. A. Lazar, “The dawn of the SPPARMs?” Science STKE, no. 121, p. PE9, 2002. View at Google Scholar
  146. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-?,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar
  147. D. M. Heery, E. Kalkhoven, S. Hoare, and M. G. Parker, “A signature motif in transcriptional co-activators mediates binding to nuclear receptors,” Nature, vol. 387, no. 6634, pp. 733–736, 1997. View at Publisher · View at Google Scholar
  148. B. D. Darimont, R. L. Wagner, J. W. Apriletti et al., “Structure and specificity of nuclear receptor-coactivator interactions,” Genes & Development, vol. 12, pp. 3343–3356, 1998. View at Google Scholar
  149. H. E. Xu, T. B. Stanley, V. G. Montana et al., “Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARa,” Nature, vol. 415, no. 6873, pp. 813–817, 2002. View at Google Scholar
  150. E. Burgermeister, A. Schnoebelen, A. Flament et al., “A novel partial agonist of peroxisome proliferator-activated receptor-? (PPAR?) recruits PPAR?-coactivator-1a, prevents triglyceride accumulation, and potentiates insulin signaling in vitro,” Molecular Endocrinology, vol. 20, no. 4, pp. 809–830, 2006. View at Publisher · View at Google Scholar
  151. A. R. Miller and G. J. Etgen, “Novel peroxisome proliferator-activated receptor ligands for type 2 diabetes and the metabolic syndrome,” Expert Opinion on Investigational Drugs, vol. 12, no. 9, pp. 1489–1500, 2003. View at Publisher · View at Google Scholar
  152. T.-A. Cock, S. M. Houten, and J. Auwerx, “Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm,” EMBO Reports, vol. 5, no. 2, pp. 142–147, 2004. View at Publisher · View at Google Scholar
  153. S. Rocchi, F. Picard, J. Vamecq et al., “A unique PPAR? ligand with potent insulin-sensitizing yet weak adipogenic activity,” Molecular Cell, vol. 8, no. 4, pp. 737–747, 2001. View at Publisher · View at Google Scholar
  154. P. Misra, R. Chakrabarti, R. K. Vikramadithyan et al., “PAT5A: a partial agonist of peroxisome proliferator-activated receptor ? is a potent antidiabetic thiazolidinedione yet weakly adipogenic,” Journal of Pharmacology and Experimental Therapeutics, vol. 306, no. 2, pp. 763–771, 2003. View at Publisher · View at Google Scholar
  155. T. J. Smith, G. D. Sempowski, H.-S. Wang, P. J. Del Vecchio, S. D. Lippe, and R. P. Phipps, “Evidence for cellular heterogeneity in primary cultures of human orbital fibroblasts,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 9, pp. 2620–2625, 1995. View at Publisher · View at Google Scholar
  156. R. J. Morris and M. A. Ritter, “Association of Thy-1 cell surface differentiation antigen with certain connective tissues in vivo,” Cell and Tissue Research, vol. 206, no. 3, pp. 459–475, 1980. View at Publisher · View at Google Scholar
  157. L. Koumas, T. J. Smith, S. Feldon, N. Blumberg, and R. P. Phipps, “Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes,” The American Journal of Pathology, vol. 163, no. 4, pp. 1291–1300, 2003. View at Google Scholar
  158. G. Gabbiani, “The myofibroblast: a key cell for wound healing and fibrocontractive diseases,” Progress in Clinical and Biological Research, vol. 54, pp. 183–194, 1981. View at Google Scholar
  159. G. D. Barish, V. A. Narkar, and R. M. Evans, “PPARδ: a dagger in the heart of the metabolic syndrome,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 590–597, 2006. View at Publisher · View at Google Scholar
  160. K. Qureshi and G. A. Abrams, “Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease,” World Journal of Gastroenterology, vol. 13, no. 26, pp. 3540–3553, 2007. View at Google Scholar
  161. M. Izumi, K. Eguchi, H. Nakamura, S. Nagataki, and T. Nakamura, “Premature fat deposition in the salivary glands associated with Sjogren syndrome: MR and CT evidence,” American Journal of Neuroradiology, vol. 18, no. 5, pp. 951–958, 1997. View at Google Scholar
  162. P. Desreumaux, O. Ernst, K. Geboes et al., “Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease,” Gastroenterology, vol. 117, no. 1, pp. 73–81, 1999. View at Publisher · View at Google Scholar