Repression of IFN-gamma expression by peroxisome proliferator-activated receptor gamma.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARgamma and that expression can be augmented over time in mitogen-activated splenocytes. PPARgamma ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARgamma ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARgamma is expressed in both murine CD4 and CD8 cells and that PPARgamma ligands directly decrease IFN-gamma expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARgamma antagonist, increases lymphocyte IFN-gamma expression. Transient transfection studies reveal that PPARgamma ligands, in a PPARgamma-dependent manner, potently repress an IFN-gamma promoter construct. Repression localizes to the distal conserved sequence of the IFN-gamma promoter. Our studies also demonstrate that PPARgamma acts on the IFN-gamma promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARgamma ligands may be related to direct inhibition of IFN-gamma by PPARgamma.
Cunard
Robyn
R
Research Service and Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System 151, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. rcunard@ucsd.edu
Eto
Yoko
Y
Muljadi
Julie T
JT
Glass
Christopher K
CK
Kelly
Carolyn J
CJ
Ricote
Mercedes
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D008024:Ligands; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D007371:Interferon-gamma