Retinoic acid inhibits the regulated expression of vascular cell adhesion molecule-1 by cultured dermal microvascular endothelial cells.

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Abstract

The regulated expression of cell adhesion molecules (CAM) on endothelial cells is central to the pathogenesis of various inflammatory processes. Retinoic acid and synthetic derivatives have been demonstrated to exert antiinflammatory effects in cutaneous diseases. To determine modes of retinoid action in the modulation of inflammatory responses, we explored effects of all-trans-retinoic acid (t-RA) on the TNFalpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in cultured human dermal microvascular endothelial cells. Pretreatment with t-RA specifically prevented TNFalpha-induced VCAM-1 expression, but not ICAM-1 and E-selectin induction. t-RA significantly reduced VCAM-1-dependent T cell binding to TNFalpha-treated human dermal microvascular endothelial cells as well. This differential modulation of TNFalpha-induced CAM expression by t-RA was reflected at steady state mRNA levels and in nuclear run-on studies. In transcriptional activation studies, the TNFalpha-mediated activation of the human VCAM-1 promoter was inhibited after t-RA treatment, while the ICAM-1 promoter activation was unaffected, indicating that the selective inhibition of CAM expression is regulated in part at the level of gene transcription. Furthermore, the transcriptional inhibition by t-RA appears to be mediated by its effects upon the activation of NF-kappaB-dependent complex formation. Analysis of protein-DNA binding assays revealed marked inhibition of specific NF-kappaB-dependent binding to the tandem NF-KB sites of the VCAM-1 promoter, but not to the functional NF-kappaB motif of the ICAM-1 promoter. The specific inhibition of cytokine-mediated VCAM-1 gene expression in vitro may provide a potential basis by which retinoids exert their biological effects at sites of inflammation in vivo.

Authors

J Gille, L L Paxton, T J Lawley, S W Caughman, R A Swerlick