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(Circulation Research. 2002;90:356.)
© 2002 American Heart Association, Inc.

Molecular Medicine

PPAR but not PPAR Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells

Brenda R. Kwak, Samir Myit, Flore Mulhaupt, Niels Veillard, Nathalie Rufer, Eddy Roosnek, François Mach

From the Division of Cardiology (B.R.K., S.M., F.M., N.V., F.M.) and Division of Immunology and Allergology (N.R., E.R.), Department of Medicine, University Hospital, Geneva Medical School, Foundation for Medical Research, Geneva, Switzerland.

Correspondence to François Mach, MD, Cardiology Division, Department of Medicine, University Hospital Geneva, Foundation for Medical Research, 64 Ave Roseraie, 1211 Geneva, Switzerland. E-mail machf{at}cmu.unige.ch

Peroxisome proliferator-activated receptors (PPARs) are essential in glucose and lipid metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as diabetes and dyslipidemia. Conversely, antidiabetic glitazones and hypolipidemic fibrate drugs, known as PPAR and PPAR ligands, respectively, reduce the process of atherosclerotic lesion formation, which involves chronic immunoinflammatory processes. Major histocompatibility complex class II (MHC-II) molecules, expressed on the surface of specialized cells, are directly involved in the activation of T lymphocytes and in the control of the immune response. Interestingly, expression of MHC-II has recently been observed in atherosclerotic plaques, and it can be induced by the proinflammatory cytokine interferon- (IFN-) in vascular cells. To explore a possible role for PPAR ligands in the regulation of the immune response, we investigated whether PPAR activation affects MHC-II expression in atheroma-associated cells. In the present study, we demonstrate that PPAR but not PPAR ligands act as inhibitors of IFN-–induced MHC-II expression and thus as repressors of MHC-II–mediated T-cell activation. All different types of PPAR ligands tested inhibit MHC-II. This effect of PPAR ligands is due to a specific inhibition of promoter IV of CIITA and does not concern constitutive expression of MHC-II. Thus, the beneficial effects of antidiabetic PPAR activators on atherosclerotic plaque development may be partly explained by their repression of MHC-II expression and subsequent inhibition of T-lymphocyte activation.

Key Words: major histocompatibility complex class II • peroxisome proliferator-activated receptors • human endothelial cells • human macrophages • T-lymphocyte proliferation

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