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Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages.
Exp Cell Res. 2008 Nov 01; 314(18):3405-14.EC

Abstract

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.

Authors+Show Affiliations

Research Laboratory on Atherosclerotic Biological and Genetic Factors, Faculty of Medicine, Monastir TN-5019, Tunisia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18823978

Citation

Souissi, Imen Jguirim, et al. "Matrix Metalloproteinase-12 Gene Regulation By a PPAR Alpha Agonist in Human Monocyte-derived Macrophages." Experimental Cell Research, vol. 314, no. 18, 2008, pp. 3405-14.
Souissi IJ, Billiet L, Cuaz-Pérolin C, et al. Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages. Exp Cell Res. 2008;314(18):3405-14.
Souissi, I. J., Billiet, L., Cuaz-Pérolin, C., Slimane, M. N., & Rouis, M. (2008). Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages. Experimental Cell Research, 314(18), 3405-14. https://doi.org/10.1016/j.yexcr.2008.09.002
Souissi IJ, et al. Matrix Metalloproteinase-12 Gene Regulation By a PPAR Alpha Agonist in Human Monocyte-derived Macrophages. Exp Cell Res. 2008 Nov 1;314(18):3405-14. PubMed PMID: 18823978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages. AU - Souissi,Imen Jguirim, AU - Billiet,Ludivine, AU - Cuaz-Pérolin,Clarisse, AU - Slimane,Mohamed-Naceur, AU - Rouis,Mustapha, Y1 - 2008/09/18/ PY - 2008/05/16/received PY - 2008/09/04/revised PY - 2008/09/04/accepted PY - 2008/10/1/pubmed PY - 2008/12/17/medline PY - 2008/10/1/entrez SP - 3405 EP - 14 JF - Experimental cell research JO - Exp. Cell Res. VL - 314 IS - 18 N2 - 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. SN - 1090-2422 UR - https://www.unboundmedicine.com/medline/citation/18823978/Matrix_metalloproteinase_12_gene_regulation_by_a_PPAR_alpha_agonist_in_human_monocyte_derived_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4827(08)00362-5 DB - PRIME DP - Unbound Medicine ER -