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

• Published in: Chemico-biological interactions Vol. 337; p. 109395
• Main Authors: Lu, Yi-En, Chen, Ying-Jung
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2021
• Subjects: Acetylation - drug effects; Binding Sites; Cell Survival - drug effects; Dermal fibroblasts; Down-Regulation - drug effects; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Matrix metalloproteinase; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 3 - genetics; Matrix Metalloproteinase 3 - metabolism; NF-kappa B - metabolism; Nitriles - pharmacology; p300; Phosphorylation - drug effects; Promoter Regions, Genetic; Resveratrol; Resveratrol - pharmacology; RNA Interference; RNA, Small Interfering - metabolism; Sulfones - pharmacology; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects; Wound healing; p300; Dermal fibroblasts; Wound healing; Matrix metalloproteinase; Resveratrol
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2021.109395

The aim of this study was to explore the signaling pathways associated with the effects of tumor necrosis factor alpha (TNF-α) on matrix metalloproteinase-1 (MMP-1) and MMP-3 expression in the human dermal fibroblast cell line CCD-966SK. TNF-α upregulated MMP-1 and MMP-3 mRNA and protein expression, and NFκB/p65 activation was found to be involved in TNF-α-induced MMP-1 and MMP-3 upregulation. TNF-α induced p65 phosphorylation at Ser536 and acetylation at Lys310. p300 knockdown suppressed TNF-α-induced p65 acetylation and reduced MMP-1 and MMP-3 expression in TNF-α-treated cells, but did not greatly restore MMP-1 and MMP-3 expression when p65 phosphorylation was inhibited by Bay11-7082 (IκBα inhibitor). NF-κB/luciferase reporter assay revealed that p300-mediated p65 acetylation was crucial for TNF-α-induced nuclear factor-kappa B (NF-κB) transcriptional activity. The chromatin immunoprecipitation (ChIP) assay indicated that TNF-α increased p300 recruitment to the MMP-1 and MMP-3 promoter regions surrounding the NFκB-binding site. Resveratrol notably inhibited TNF-α-induced MMP-1 and MMP-3 upregulation and abrogated TNF-α-induced p65 acetylation, leading to the downregulation of MMP-1 and MMP-3 expression in TNF-α-treated cells. Our data indicate that TNF-α-induced p300-mediated p65 acetylation leads to the upregulation of MMP-1 and MMP-3 expression in dermal fibroblasts, whereas resveratrol reduces this TNF-α-induced upregulation by downregulating p300 expression. [Display omitted] •TNF-α-induced MMP-1/MMP-3 expression via p300-NFκB acetylation signaling pathways.•Resveratrol decrease the acetyltransferase activity of p300.•Resveratrol restores TNF-a-induced MMP-1/MMP-3 expression in human fibroblasts.