The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses.
The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors belonging to the nuclear receptor superfamily. Until recently, the genes regulated by PPARs were those believed to be predominantly associated with lipid metabolism. Recently, an immunomodulatory role for PPAR gamma has been described in cells critical to the innate immune system, the monocyte/macrophage. In addition, evidence for an antiinflammatory role of the PPAR gamma ligand, 15-deoxy-Delta 12,14-PGJ2 (15d-PGJ2) has been found. In the present studies, we demonstrate, for the first time, that murine helper T cell clones and freshly isolated splenocytes express PPAR gamma 1. The PPAR gamma expressed is of functional significance in that two ligands for PPAR gamma, 15d-PGJ2 and a thiazolidinedione, ciglitazone, mediate significant inhibition of proliferative responses of both the T cell clones and the freshly isolated splenocytes. This inhibition is mediated directly at the level of the T cell and not at the level of the macrophage/APC. Finally, we demonstrate that the two ligands for PPAR gamma mediate inhibition of IL-2 secretion by the T cell clones while not inhibiting IL-2-induced proliferation of such clones. The demonstration of the expression and function of PPAR gamma in T cells reveals a new level of immunoregulatory control for PPARs and significantly increases the role and importance of PPAR gamma in immunoregulation.
Clark
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RB
Division of Rheumatic Diseases, Department of Medicine, University of Connecticut Medical School, Farmington, CT 06032, USA. rclark@nso2.uchc.edu
Bishop-Bailey
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D
Estrada-Hernandez
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T
Hla
T
T
Puddington
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L
Padula
S J
SJ
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001666:Binding Sites, Antibody / Q000187:drug effects; D017252:CD3 Complex / Q000276:immunology; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D007106:Immune Sera / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008830:Microbodies / Q000276:immunology / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000276:Adjuvants, Immunologic; D017252:CD3 Complex; D007106:Immune Sera; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D015230:Prostaglandin D2; C039671:ciglitazone