Journal
CIRCULATION RESEARCH
Volume 90, Issue 3, Pages 356-362Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh0302.104924
Keywords
major histocompatibility complex class II peroxisome proliferator-activated receptors; human endothelial cells; human macrophages; T-lymphocyte proliferation
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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 PPARgamma and PPARalpha ligands, respectively, reduce the process of atherosclerotic lesion formation, which involves chronic immunoinflammatory processes. Major histocompatibility complex class 11 (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-gamma (IFN-gamma) 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-11 expression in atheroma-associated cells. In the present study, we demonstrate that PPARgamma but not PPARa ligands act as inhibitors of IFN-gamma-induced MHC-11 expression and thus as repressors of MHC-II-mediated T-cell activation. All different types of PPARgamma ligands tested inhibit MHC-11. This effect of PPARgamma ligands is due to a specific inhibition of promoter IV of CIITA and does not concern constitutive expression of MHC-11. Thus, the beneficial effects of antidiabetic PPAR-gamma activators on atherosclerotic plaque development may be partly explained by their repression of MHC-11 expression and subsequent inhibition of T-lymphocyte activation.
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