Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages.
MMP-12, a macrophage-specific matrix metalloproteinase with large substrate specificity, has been reported to be highly expressed in mice, rabbits and human atherosclerotic lesions. Increased MMP-12 from inflammatory macrophages is associated with several degenerative diseases such as atherosclerosis. In this manuscript, we show that IL-1beta, a proinflammatory cytokine found in atherosclerotic plaques, increases both mRNA and protein levels of MMP-12 in human monocyte-derived macrophages (HMDM). Since peroxisome proliferator-activated receptors (PPARs), such as PPARalpha and PPARgamma, are expressed in macrophages and because PPAR activation exerts an anti-inflammatory effect on vascular cells, we have investigated the effect of PPARalpha and gamma isoforms on MMP-12 regulation in HMDM. Our results show that MMP-12 expression (mRNA and protein) is down regulated in IL-1beta-treated macrophages only in the presence of a specific PPARalpha agonist, GW647, in a dose-dependent manner. In contrast, this inhibitory effect was abolished in IL-1beta-stimulated peritoneal macrophages isolated from PPARalpha(-/-) mice and treated with the PPARalpha agonist, GW647. Moreover, reporter gene transfection experiments using different MMP-12 promoter constructs showed a reduction of the promoter activities by approximately 50% in IL-1beta-stimulated PPARalpha-pre-treated cells. However, MMP-12 promoter analysis did not reveal the presence of a PPRE response element. The IL-1beta effect is known to be mediated through the AP-1 binding site. Mutation of the AP-1 site, located at -81 in the MMP-12 promoter region relative to the transcription start site, followed by transfection analysis, gel shift and ChIP experiments revealed that the inhibitory effect was the consequence of the protein-protein interaction between GW 647-activated PPARalpha and c-Fos or c-Jun transcription factors, leading to inhibition of their binding to the AP-1 motif. These studies suggest that PPARalpha agonists may be used therapeutically, not only for lipid disorders, but also to prevent inflammation and atheromatous plaque rupture, where their ability to inhibit MMP-12 expression in HMDM may be beneficial.
Souissi
Imen Jguirim
IJ
Research Laboratory on Atherosclerotic Biological and Genetic Factors, Faculty of Medicine, Monastir TN-5019, Tunisia.
Billiet
Ludivine
L
Cuaz-Pérolin
Clarisse
C
Slimane
Mohamed-Naceur
MN
Rouis
Mustapha
M
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology*; D047493:PPAR alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis
D053583:Interleukin-1beta; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D053508:Matrix Metalloproteinase 12