Pigment epithelium-derived factor induces THP-1 macrophage apoptosis and necrosis by the induction of the peroxisome proliferator-activated receptor gamma

Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor, partially through the induction of endothelial cell apoptosis. Here we report that PEDF can also induce the apoptosis of human THP-1 monocytic leukemia cell line-derived macrophage cells (THP-1 macrophages) and peroxisome proliferator-activated receptor gamma (PPAR gamma), a pleiotropic transcriptional factor is involved in the signaling. TUNEL and propidium iodide permeability assays demonstrated that PEDF dose- and time-dependently induces both apoptosis and necrosis of THP-1 macrophages while inducing the cleavages of procaspase-9, -3, the release of cytochrome c and the overexpression of p53. All these PEDF effects can be attenuated by either PPAR gamma inhibitor GW9662 or PPAR gamma small interfering RNA. The effects of PEDF can be reproduced by transient expression of PPAR gamma by a PPAR gamma-expression plasmid transfection. PEDF increased the expression and transcriptional activity of PPAR gamma in THP-1 macrophages. In addition, PEDF also induced apoptosis in primary human monocyte-derived macrophages (MDMs) while inducing the expression of PPAR gamma. Our observations indicate that PEDF induces macrophage apoptosis and necrosis through the signaling of PPAR gamma. This suggests a novel mechanism through which PEDF can modulate inflammation. (c) 2007 Elsevier Ltd. All rights reserved.