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. Our results showed that IL-1b, a proinflammatory cytokine found in atherosclerotic plaques, increased both mRNA and protein levels of MMP-12 in human monocyte-derived macrophages (HMDM). Since peroxisome proliferator-activated receptors (PPAR) such as PPARa and PPARg are expressed in macrophages and because PPARs activation exert an anti-inflammatory effect on vascular cells; we have investigated the effect of PPARa and g isoforms on MMP-12 regulation in HMDM. Our results showed that MMP-12 expression (mRNA and protein) was down regulated in IL-1b-treated macrophages only in the presence of a specific PPARa agonist GW647 in a dose-dependent manner. In contrast, this inhibitory effect was abolished in IL-1b-stimulated peritoneal macrophages isolated from PPARa-/- mice and treated with the GW647 PPARa agonist. Moreover, reporter gene transfection experiments using different MMP-12 promoter constructs showed a reduction of the promoter activities by 50 % in IL-1b-stimulated PPARa pretreated cells. However, MMP-12 promoter analysis did not reveal the presence of a PPRE response element. The IL-1b effect is known to be mediated through the AP-1 binding site. Mutation of the AP-1 site, which is located at -81 in the MMP-12 promoter region relative to the transcription start site, followed by transfection analysis and gel shift experiments revealed that the inhibitory effect was the consequence of the protein-protein interaction between GW 647-activated PPARa and c-Fos or c-Jun transcription factors, leading to inhibition of their binding to the AP-1 motif. These studies suggest that PPARa agonists may be used as a 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.