Role of T cells and PPARgamma in Graves' orbital fibroblast adipogenesis

Summary

Principal Investigator: Richard Phipps
Abstract: DESCRIPTION (provided by applicant): Thyroid associated ophthalmopathy (TAO, also called Graves'ophthalmopathy) is a serious autoimmune disease involving orbital tissue inflammation. Orbital tissue is infiltrated mainly by T lymphocytes and contains proinflammatory cytokines and prostaglandins. A hallmark of TAO is an increase in orbital fat that pushes the eye out of the orbit (proptosis). TAO is disfiguring and may lead to blindness. Pre-adipocyte orbital fibroblasts are key effector cells in this process. Orbital inflammation is postulated to drive their differentiation to fat cells called adipocytes. The inflammatory signals that induce this differentiation remain an important, yet poorly studied aspect of TAO. Adipocytic differentiation is believed to be mainly controlled by a transcription factor called peroxisome proliferator activated receptor gamma (PPARgamma). Our research shows that human orbital fibroblasts highly express PPARgamma and that both natural (15d-PGJ2) and synthetic (e.g. the insulin-sensitizing drugs rosiglitazone) PPARgamma ligands induce a subset of Graves'orbital fibroblasts to differentiate to adipocytes. Our compelling new data show that circulating T lymphocytes from Graves'patients'highly express the prostaglandin-generating enzyme cycloxygenase-2 (Cox-2) and produce the PPARgamma ligand 15d-PGJ2. Moreover, Graves'T cells drive a subset of PPARgamma expressing TAO fibroblasts to adipocytes. These exciting data are the first to demonstrate that human T cells produce a functional PPARgamma ligand and supports that the process of orbital inflammation drives adipogenesis. The overall hypothesis we will test is that Graves'T lymphocytes produce a PPARgamma ligand that induces a subset of PPARgamma expressing orbital fibroblasts to differentiate to adipocytes. The following three questions posed as specific aims will be answered to test the overall hypothesis. Aim 1: Are Graves'disease human T lymphocytes unique in their ability to highly express Cox-2 and produce prostaglandins (e.g. 15d-PGJ2) that act as PPARgamma ligands? Aim 2: Is the ability of Graves'orbital fibroblasts to differentiate to adipocytes dependent on the pro-adipogenic transcription factor PPARgamma? Aim 3: What are the differences between Thy1+ and Thy1- Graves'orbital fibroblasts that determine why only ThyT fibroblasts differentiate to adipocytes? These studies will help delineate the inflammatory cells and pathways that incite orbital fibroblast differentiation to adipocytes. This new information will permit the development of new approaches to control inflammation and the pathologic differentiation of orbital fibroblasts important for TAO and other diseases that involve fat deposition.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi More than structural cells, fibroblasts create and orchestrate the tumor microenvironment
    Carolyn J Baglole
    Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, and Lymphoma Biology Program, James P Wilmot Cancer Center, Rochester, New York 14642, USA
    Immunol Invest 35:297-325. 2006
  2. pmc Topical rosiglitazone is an effective anti-scarring agent in the cornea
    Krystel R Huxlin
    Flaum Eye Institute, University of Rochester, Rochester, New York, United States of America
    PLoS ONE 8:e70785. 2013
  3. pmc The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis
    Ajit A Kulkarni
    The Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, Rochester, New York, United States of America
    PLoS ONE 8:e63798. 2013
  4. pmc Inhibitory effects of PPARγ ligands on TGF-β1-induced corneal myofibroblast transformation
    Kye Im Jeon
    Flaum Eye Institute, University of Rochester, Rochester, New York
    Am J Pathol 184:1429-45. 2014
  5. pmc The eye and thyroid disease
    Ajay E Kuriyan
    University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
    Curr Opin Ophthalmol 19:499-506. 2008
  6. pmc 15-deoxy-delta12,14-PGJ2 enhances platelet production from megakaryocytes
    Jamie J O'Brien
    Department of Environmental Medicine and the Lung Biology and Disease Program, University of Rochester, NY, USA
    Blood 112:4051-60. 2008
  7. pmc Immune mechanisms in thyroid eye disease
    Geniece M Lehmann
    Department of Environmental Medicine, University of Rochester, Rochester, New York 14642, USA
    Thyroid 18:959-65. 2008
  8. pmc Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise
    M P Bernard
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Curr Pharm Des 14:2051-60. 2008
  9. pmc Improvement of thyroid eye disease following treatment with the cyclooxygenase-2 selective inhibitor celecoxib
    Ajay E Kuriyan
    Thyroid 18:911-4. 2008
  10. pmc Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes
    Steven E Feldon
    Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA
    Am J Pathol 169:1183-93. 2006

Scientific Experts

  • Holly B Hindman
  • Richard P Phipps
  • Steven E Feldon
  • Patricia J Sime
  • Geniece M Lehmann
  • Krystel R Huxlin
  • Carolyn J Baglole
  • Thomas H Thatcher
  • Naxin Guo
  • Heather E Ferguson
  • Charles W O'Loughlin
  • Ajay E Kuriyan
  • Kye Im Jeon
  • Ajit A Kulkarni
  • Collynn F Woeller
  • Keith C Olsen
  • Xia Xi
  • Jens Bühren
  • Stephen J Pollock
  • Terry J Smith
  • Kathryn E Seweryniak
  • A E Kuriyan
  • Ajit Kulkarni
  • Scott Macrae
  • Shikha Gupta
  • R P Phipps
  • Ruotian Jiang
  • Seongmu Lee
  • Richard T Libby
  • P J Sime
  • Robert A Goldberg
  • Raymond S Douglas
  • Tatiana M Garcia-Bates
  • Catherine J Hwang
  • Kurt M Bertram
  • Jamie J Bernard
  • Mark B Taubman
  • Sherry L Spinelli
  • James Palis
  • Charles W Francis
  • Neil Blumberg
  • Jamie J O'Brien
  • M P Bernard
  • Samuel Caito
  • Denise M Ray
  • Margaret Demagistris
  • Hsi Min Hsiao
  • Terry W Wright
  • Robert Matthew Kottmann
  • David Ciufo
  • Jason Morrissette
  • C F Woeller
  • G M Lehmann
  • K R Huxlin
  • S E Feldon
  • A A Kulkarni
  • David H McMillan
  • Ann E Casey
  • Adeline Martz
  • Kelvin Chong
  • Ronald Mancini
  • Antoine Taly
  • Lia Prado de Carvalho
  • Sophie Gonin
  • Mehryar Taban
  • Thomas Grutter
  • Shawn Kenner
  • Emily R Strong
  • Anne D Koniski
  • R M Kottmann
  • Lana Nagy
  • Jonathan Said
  • Daniel Sand
  • Jennifer N Swanton
  • Nikoo Afifiyan
  • Vibha Naik
  • Beiling Chen
  • Indika Edirisinghe
  • Saravanan Rajendrasozhan
  • Joanna Tober
  • Aruna Kode
  • Jacqueline M Gertz
  • Se Ran Yang
  • Irfan Rahman
  • S Bancos
  • Heather F Lakatos
  • Thomas A Gasiewicz
  • Sanjay B Maggirwar
  • Steven H Bernstein
  • Shira Landskroner-Eiger

Detail Information

Publications28

  1. ncbi More than structural cells, fibroblasts create and orchestrate the tumor microenvironment
    Carolyn J Baglole
    Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, and Lymphoma Biology Program, James P Wilmot Cancer Center, Rochester, New York 14642, USA
    Immunol Invest 35:297-325. 2006
    ..This review will highlight the emerging role of the complex fibroblastic stroma in establishing a microenvironment supporting malignant transformation, tumor growth and attenuation of host anti-tumor immune responses...
  2. pmc Topical rosiglitazone is an effective anti-scarring agent in the cornea
    Krystel R Huxlin
    Flaum Eye Institute, University of Rochester, Rochester, New York, United States of America
    PLoS ONE 8:e70785. 2013
    ..Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas...
  3. pmc The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis
    Ajit A Kulkarni
    The Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, Rochester, New York, United States of America
    PLoS ONE 8:e63798. 2013
    ..g. chemotherapy and radiation) and by systemic autoimmune diseases...
  4. pmc Inhibitory effects of PPARγ ligands on TGF-β1-induced corneal myofibroblast transformation
    Kye Im Jeon
    Flaum Eye Institute, University of Rochester, Rochester, New York
    Am J Pathol 184:1429-45. 2014
    ..Thus, the PPARγ ligands tested here showed great promise as antifibrotics, both in vitro and in vivo. Our results also provided new evidence for the signaling pathways that may underlie these antifibrotic actions in corneal fibroblasts...
  5. pmc The eye and thyroid disease
    Ajay E Kuriyan
    University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
    Curr Opin Ophthalmol 19:499-506. 2008
    ..Recent studies have increased our knowledge of the disease process and different diagnostic and therapeutic options. This review highlights the recent progress in TED research and identifies areas requiring further advancements...
  6. pmc 15-deoxy-delta12,14-PGJ2 enhances platelet production from megakaryocytes
    Jamie J O'Brien
    Department of Environmental Medicine and the Lung Biology and Disease Program, University of Rochester, NY, USA
    Blood 112:4051-60. 2008
    ....
  7. pmc Immune mechanisms in thyroid eye disease
    Geniece M Lehmann
    Department of Environmental Medicine, University of Rochester, Rochester, New York 14642, USA
    Thyroid 18:959-65. 2008
    ....
  8. pmc Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise
    M P Bernard
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Curr Pharm Des 14:2051-60. 2008
    ..Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies...
  9. pmc Improvement of thyroid eye disease following treatment with the cyclooxygenase-2 selective inhibitor celecoxib
    Ajay E Kuriyan
    Thyroid 18:911-4. 2008
  10. pmc Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes
    Steven E Feldon
    Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA
    Am J Pathol 169:1183-93. 2006
    ..They also suggest the possibility that, in addition to the orbit, T lymphocytes influence the deposition of fat in other tissues...
  11. pmc Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB
    Thomas H Thatcher
    Department of Medicine, University of Rochester, Rochester, New York 14642, USA
    Am J Pathol 170:855-64. 2007
    ....
  12. ncbi Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages
    Samuel Caito
    Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York 14642 USA
    Antioxid Redox Signal 10:253-60. 2008
    ..These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis...
  13. pmc Novel anti-adipogenic activity produced by human fibroblasts
    Geniece M Lehmann
    Dept of Environmental Medicine, Univ of Rochester, Rochester, NY, USA
    Am J Physiol Cell Physiol 299:C672-81. 2010
    ..It is possible that such a factor plays an important role in the prevention of excess fat deposition in the normal orbit and may even be exploited as a therapy for the treatment of obesity, a major worldwide health concern...
  14. pmc The aryl hydrocarbon receptor ligand ITE inhibits TGFβ1-induced human myofibroblast differentiation
    Geniece M Lehmann
    Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
    Am J Pathol 178:1556-67. 2011
    ..As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent...
  15. pmc Peroxisome proliferator-activated receptor gamma ligands inhibit transforming growth factor-beta-induced, hyaluronan-dependent, T cell adhesion to orbital fibroblasts
    Naxin Guo
    Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Biol Chem 286:18856-67. 2011
    ..Pio and Rosi exhibit anti-fibrotic and anti-inflammatory activity and may be useful in treating thyroid eye disease...
  16. pmc Ocular fibroblast diversity: implications for inflammation and ocular wound healing
    Xia Xi
    Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Invest Ophthalmol Vis Sci 52:4859-65. 2011
    ..The hypothesis for this study was that that human fibroblasts derived from distinct ocular tissues differ in their responses to IL-1β and that variations in the IL-1 signaling pathway account for these differences...
  17. pmc Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring
    A E Kuriyan
    University of Rochester School of Medicine and Dentistry, University of Rochester, Rochester, NY, United States
    Exp Eye Res 94:136-45. 2012
    ....
  18. pmc A putative extracellular salt bridge at the subunit interface contributes to the ion channel function of the ATP-gated P2X2 receptor
    Ruotian Jiang
    Laboratoire de Biophysicochimie des Récepteurs Canaux, UMR 7199 CNRS, Conception et Application de Molécules Bioactives, Faculte de Pharmacie, Universite de Strasbourg, 74 route du Rhin, BP 24, 67401 Illkirch Cedex, France
    J Biol Chem 285:15805-15. 2010
    ....
  19. pmc Mast cell-derived prostaglandin D2 controls hyaluronan synthesis in human orbital fibroblasts via DP1 activation: implications for thyroid eye disease
    Naxin Guo
    Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Biol Chem 285:15794-804. 2010
    ..Mast cell-derived PGD(2) increased HA production via activation of DP1. Selectively targeting the production of PGD(2) and/or activation of DP1 may prevent pathological changes associated with TED...
  20. ncbi Endoscopic removal of nasoglabellar dermoid cysts
    Seongmu Lee
    Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at University of California Los Angeles, California, USA
    Ophthal Plast Reconstr Surg 26:136-9. 2010
    ..The authors describe 2 cases using a hidden hairline incision and an endoscopic approach to remove dermoid cysts in the nasoglabellar region...
  21. pmc Differences in the TGF-{beta}1-induced profibrotic response of anterior and posterior corneal keratocytes in vitro
    Holly B Hindman
    Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York, USA
    Invest Ophthalmol Vis Sci 51:1935-42. 2010
    ..This heterogeneity of keratocyte response may impact wound closure after mechanical wounding...
  22. pmc Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism
    Heather E Ferguson
    Department of Environmental Medicine, University of Rochester, 601 Elmwood Ave, Box 692, Rochester, NY 14642, USA
    Am J Physiol Lung Cell Mol Physiol 297:L912-9. 2009
    ....
  23. pmc Foxp3 regulates megakaryopoiesis and platelet function
    Jamie J Bernard
    Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
    Arterioscler Thromb Vasc Biol 29:1874-82. 2009
    ..Scurfy mice and some humans with IPEX are also thrombocytopenic. The purpose of this study was to determine whether the absence of functional Foxp3 leads to defects in megakaryocytes and platelets...
  24. pmc Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts
    Heather E Ferguson
    Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
    Am J Respir Cell Mol Biol 41:722-30. 2009
    ..As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high...
  25. pmc Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1
    Catherine J Hwang
    Jules Stein Eye Institute, University of California at Los Angeles, Los Angeles, California, USA
    Invest Ophthalmol Vis Sci 50:2262-8. 2009
    ..In the present study the authors investigated the role of CD40 ligation on macrophage chemoattractant protein-1 (MCP-1), IL-6, and IL-8 expression in fibroblasts from patients with TAO...
  26. pmc Optical effects of anti-TGFbeta treatment after photorefractive keratectomy in a cat model
    Jens Bühren
    University of Rochester Eye Institute, University of Rochester, Rochester, New York 14642, USA
    Invest Ophthalmol Vis Sci 50:634-43. 2009
    ..To assess the contribution of corneal myofibroblasts to optical changes induced by photorefractive keratectomy (PRK) in a cat model...
  27. pmc Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration
    Kurt M Bertram
    Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Am J Physiol Cell Physiol 297:C1200-10. 2009
    ..These data support the hypothesis that cigarette smoke contributes to AMD pathogenesis by causing oxidative damage and cell death to RPE cells...