Resveratrol inhibits matrix metalloproteinase-1 and-3 expression by suppressing of p300/NFκB acetylation in TNF-α-treated human dermal fibroblasts

The aim of this study was to explore the signaling pathways associated with the effects of tumor necrosis factor alpha (TNF-alpha) on matrix metalloproteinase-1 (MMP-1) and MMP-3 expression in the human dermal fibroblast cell line CCD-966SK. TNF-alpha upregulated MMP-1 and MMP-3 mRNA and protein expression, and NF-kappa B/p65 activation was found to be involved in TNF-alpha-induced MMP-1 and MMP-3 upregulation. TNF-alpha induced p65 phosphorylation at Ser536 and acetylation at Lys310. p300 knockdown suppressed TNF-alpha-induced p65 acetylation and reduced MMP-1 and MMP-3 expression in TNF-alpha-treated cells, but did not greatly restore MMP-1 and MMP-3 expression when p65 phosphorylation was inhibited by Bayl 1-7082 (I kappa B alpha inhibitor). NF-kappa B/luciferase reporter assay revealed that p300-mediated p65 acetylation was crucial for TNF-alpha-induced nuclear factor-kappa B (NF-kappa B) transcriptional activity. The chromatin immunoprecipitation (ChIP) assay indicated that TNF-alpha increased p300 recruitment to the MMP-1 and MMP-3 promoter regions surrounding the NFO-binding site. Resveratrol notably inhibited TNF-alpha-induced MMP-1 and MMP-3 upregulation and abrogated TNF-alpha-induced p65 acetylation, leading to the downregulation of MMP-1 and MMP-3 expression in TNF-alpha-treated cells. Our data indicate that TNF-alpha-induced p300-mediated p65 acetylation leads to the upregulation of MMP-1 and MMP-3 expression in dermal fibroblasts, whereas resveratrol reduces this TNF-alpha-induced upregulation by downregulating p300 expression.