Activation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophages

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPAR alpha and PPAR gamma forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPAR alpha is already present in undifferentiated monocytes, PPAR gamma expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPAR alpha resides constitutively in the cytoplasm, whereas PPAR gamma is predominantly nuclear localized. Transient transfection experiments indicate that PPAR alpha and PPAR gamma are transcriptionally active after ligand stimulation. Ligand activation of PPAR gamma, but not of PPAR alpha, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPAR alpha and PPAR gamma ligands induce apoptosis of macrophages activated with tumor necrosis factor alpha/interferon gamma. Finally, PPAR gamma inhibits the transcriptional activity of the NF kappa B p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NF kappa B signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.