Activation of Proliferator-activated Receptors α and γ Induces Apoptosis of Human Monocyte-derived Macrophages

doi:10.1074/jbc.273.40.25573

Activation of Proliferator-activated Receptors α and γ Induces Apoptosis of Human Monocyte-derived Macrophages*

From ^‡U.325 INSERM, Département d’Athérosclérose, Institut Pasteur, 1 Rue Calmette, 59019 Lille, France, the Faculté de Pharmacie, Université de Lille II, 59006 Lille, France, and ^¶U.321 INSERM, Hôpital de la Pitié, 83 Boulevard de l’Hôpital, F-75651 Paris, Cedex 13, France

Abstract

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 PPARα and PPARγ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARα is already present in undifferentiated monocytes, PPARγ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARα resides constitutively in the cytoplasm, whereas PPARγ is predominantly nuclear localized. Transient transfection experiments indicate that PPARα and PPARγ are transcriptionally active after ligand stimulation. Ligand activation of PPARγ, but not of PPARα, 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 PPARα and PPARγ ligands induce apoptosis of macrophages activated with tumor necrosis factor α/interferon γ. Finally, PPARγ inhibits the transcriptional activity of the NFκB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFκB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.

Footnotes

↵* This work was supported by grants from the Région Nord-Pas de Calais, the University of Milan (to G. C.), French Ministery of Research and Technology Grant MRT 25CIA036A, the Group Lipides et Nutrition, and EU-Biomed 2 program Grant PL963324.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Contributed equally to the results of this work.
↵‖ Member of the CNRS. To whom correspondence should be addressed: U.325 INSERM, Institut Pasteur de Lille, 1 Rue Calmette BP245, 59019 Lille, France. Tel.: 33-3-20-87-73-88; Fax: 33-3-20-87-73-60; E-mail: Bart.Staels{at}pasteur-lille.fr.
Abbreviations:

PPAR

peroxisome proliferator-activated receptor

PPRE

peroxisome proliferator response element

IFNγ

interferon γ

TNFα

tumor necrosis factor α

RT-PCR

reverse transcriptase-polymerase chain reaction

bp

base pair(s)

PBS

phosphate-buffered saline

PG-J2

prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂.
- Received March 31, 1998.
- Revision received June 27, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.