Activation of proliferator-activated receptors alpha and gamma 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 PPARalpha and PPARgamma forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARalpha is already present in undifferentiated monocytes, PPARgamma expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARalpha resides constitutively in the cytoplasm, whereas PPARgamma is predominantly nuclear localized. Transient transfection experiments indicate that PPARalpha and PPARgamma are transcriptionally active after ligand stimulation. Ligand activation of PPARgamma, but not of PPARalpha, 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 PPARalpha and PPARgamma ligands induce apoptosis of macrophages activated with tumor necrosis factor alpha/interferon gamma. Finally, PPARgamma inhibits the transcriptional activity of the NFkappaB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFkappaB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.
Chinetti
G
G
U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, 1 Rue Calmette, 59019 Lille, France.
Griglio
S
S
Antonucci
M
M
Torra
I P
IP
Delerive
P
P
Majd
Z
Z
Fruchart
J C
JC
Chapman
J
J
Najib
J
J
Staels
B
B
D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D007371:Interferon-gamma / Q000494:pharmacology; D008024:Ligands; D008264:Macrophages / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008024:Ligands; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma; C006253:pirinixic acid; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases