Published online before print January 10, 2002, doi: 10.1161/hh0302.104924
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Submitted on August 9, 2001
Revised on November 30, 2001
Accepted on December 21, 2001
PPAR
but not PPAR
Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells
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.
* To whom correspondence should be addressed. 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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