RETINOIC ACID INHIBITS THE REGULATED EXPRESSION OF VASCULAR CELL-ADHESION MOLECULE-1 BY CULTURED DERMAL MICROVASCULAR ENDOTHELIAL-CELLS

The regulated expression of cell adhesion molecules (CAM) on endotheli al cells is central to the pathogenesis of various inflammatory proces ses. Retinoic acid and synthetic derivatives have been demonstrated to exert antiinflammatory effects in cutaneous diseases. To determine mo des of retinoid action in the modulation of inflammatory responses, we explored effects of all-trans-retinoic acid (t-RA) on the TNF alpha-i nduced expression of vascular cell adhesion molecule-1 (VCAM-1), inter cellular adhesion molecule-1 (ICAM-1), and E-selectin in cultured huma n dermal microvascular endothelial cells. Pretreatment with t-RA speci fically prevented TNF alpha-induced VCAM-1 expression, but not ICAM-1 and E-selectin induction, t-RA significantly reduced VCAM-1-dependent T cell binding to TNF-alpha-treated human dermal microvascular endothe lial cells as well. This differential modulation of TNF alpha-induced CAM expression by t-RA was reflected at steady state mRNA levels and i n nuclear run-on studies. In transcriptional activation studies, the T NF alpha-mediated activation of the human VCAM-1 promoter was inhibite d after t-RA treatment, while the ICAM-1 promoter activation was unaff ected, indicating that the selective inhibition of CAM expression is r egulated in part at the level of gene transcription. Furthermore, the transcriptional inhibition by t-RA. appears to be mediated by its effe cts upon the activation of NF-kappa B-dependent complex formation. Ana lysis of protein-DNA binding assays revealed marked inhibition of spec ific NF-kappa E-dependent binding to the tandem NF-kappa B sites of th e VCAM-1 promoter, but not to the functional NF-kappa B moth of the IC AM-1 promoter, The specific inhibition of cytokine-mediated VCAM-1 gen e expression in vitro may provide a potential basis by which retinoids exert their biological effects at sites of inflammation in vivo.