Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma.
The effect of resveratrol on macrophage EMMPRIN expression and its potential mechanism was investigated. Both EMMPRIN expression and MMP-9 activity, respectively assayed by Western blot and zymography, were greatly up-regulated during PMA-induced macrophage differentiation from THP-1 monocytes. Both resveratrol and a PPARgamma agonist, pioglitazone, significantly inhibited EMMPRIN expression and MMP-9 activity in a concentration-dependent manner. The effects of pioglitazone and resveratrol were reversed by pretreatment of THP-1 cells with a PPARgamma antagonist, GW9662, prior to PMA induction. Thus, data suggest that resveratrol may down-regulate EMMPRIN and MMP-9 through PPARgamma activation. This possibility was further examined in resveratrol-or pioglitazone-treated U937 cells, which had been co-transfected with a PPARgamma expression vector and a luciferase reporter vector containing three tandem repeats of PPRE in cis. Results of the agonist-activated luciferase assay showed that resveratrol activated PPARgamma in a concentration-dependent manner. Since EMMPRIN and MMP-9 up-regulation is associated with activation of the NF-kappaB pathway, we investigated the effect of pioglitazone and resveratrol on TNF-alpha-induced NF-kappaB activation. Western blot results indicated that both pioglitazone and resveratrol markedly inhibited the NF-kappaB pathway through suppressing IkappaB protein phosphorylation in macrophages, although this effect of resveratrol was not reversed by GW9662. In conclusion, resveratrol can down-regulate EMMPRIN expression by macrophages via activating PPARgamma. This may be a primary mechanism of its inhibitory effect on MMP-9.
Ge
Heng
H
Department of Cardiology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhang
Jun-Feng
JF
Guo
Bing-Shi
BS
He
Qing
Q
Wang
Bin-Yao
BY
He
Ben
B
Wang
Chang-Qian
CQ
D000813:Anilides / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051926:Basigin / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; C497886:BSG protein, human; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D013267:Stilbenes; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D051926:Basigin; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol; D000077205:Pioglitazone