EFFICIENT INHIBITION OF ACTIVATION-INDUCED FAS LIGAND UP-REGULATION AND T-CELL APOPTOSIS BY RETINOIDS REQUIRES OCCUPANCY OF BOTH RETINOID-X RECEPTORS AND RETINOIC ACID RECEPTORS

Two retinoic acid (RA) receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been identified. All-trans-RA and its 9-cis-isomer are ligands for RARs, but only 9-cis-RA binds RXRs with high affinity, Activation-induced T cell hybridoma death is mediated via the engagement of Fas by activation-up-regulated Fas ligand, and RA prevents this type of apoptosis by inhibiting the induction of Fas ligand expression. To investigate the mechanism of RA action, T hybridoma cells were transfected with cDNA encoding RXR beta or dominant-negative RXR beta. Cells that overexpressed RXR beta were more sensitive to 9-cis-RA rescue from activation-induced death than cells transfected with vector alone, In contrast, cells expressing the dominant-negative RXR beta could not be rescued from death with 9-cis-RA. In wild type cells, an RAR-selective synthetic retinoid had little effect on activation-induced apoptosis, while an RXR-selective agonist prevented apoptosis but only at concentrations about similar to 10-fold greater than that required for 9-cis-RA. Simultaneous addition of the RAR- and RXR-selective retinoids completely prevented activation-induced apoptosis at concentrations where either alone had relatively little protective effect, The same hierarchy of efficacy was found for activation-induced Fas ligand expression, These data demonstrate that binding of both RARs and RXRs is required for efficient inhibition of activation-induced Fas ligand up-regulation and T cell apoptosis by retinoic acid.