All‐trans retinoic acid increases matrix metalloproteinase‐9 expression in murine myeloid dendritic cells through retinoic acid receptor‐α interaction with and histone acetylation of the promoter

Abstract

Myeloid dendritic cells (DC) are antigen presenting cells that migrate to secondary lymphoid tissues following activation. We have previously shown that treatment of mouse DC with all‐trans retinoic acid (atRA) decreases adherence through production and activity of matrix metalloproteinase (MMP)‐9. The Mmp‐9 promoter does not, however, contain a traditional retinoic acid response element for atRA to transduce its signal for gene regulation. To identify the mechanism by which atRA increases MMP‐9 production in DC, we performed electrophoretic mobility shift assays for the consensus Sp1, AP‐1 and NFκB binding sites located in the Mmp‐9 promoter. We found no consistent change in nuclear protein binding to Sp1 or AP‐1 consensus sequences in response to atRA, while binding to NFκB decreased compared to retinoic acid receptor (RAR)‐alpha antagonist treatment. We next performed chromatin immunoprecipitation assays to assess the effect of atRA on Mmp‐9 promoter activity. We found that atRA increased recruitment of RARα (38%) and histone acetyltransferase p300 (24%) to the Mmp‐9 promoter and increased histone H3 acetylation in the promoter by 29%. We conclude that atRA increases transcription of Mmp‐9 directly by enhancing RARα promoter binding, recruitment of p300, and subsequent acetylation of histone H3. Supported by the Department of Food Science and Human Nutrition, Michigan State University.Grant Funding Source: Department of Food Science and Human Nutrition, Michigan State University