INHIBITION OF ACTIVATION-INDUCED APOPTOSIS OF THYMOCYTES BY ALL-TRANS-RETINOIC AND 9-CIS-RETINOIC ACID IS MEDIATED VIA RETINOIC ACID RECEPTOR-ALPHA

Thymocytes can be induced to undergo apoptotic cell death by activatio n through the T-cell receptor (TCR). This process requires macromolecu lar synthesis and has been shown to be inhibited by retinoic acids (RA s). Two groups of nuclear receptors for RAs have been identified: reti noic acid receptors (RARs) and retinoid X receptors (RXRs). All-trans- RA is the high-affinity ligand for RARs, and 9-cis-RA additionally bin ds to RXRs with high affinity. Because 9-cis-RA is much more potent in inhibiting TCR-mediated death than all-trans-RA, it was suggested tha t RXRs participate in the process. In the present study various synthe tic retinoid analogues were used to address this question further. The results presented suggest that the inhibitory effect of RAs on activa tion-induced death of thymocytes is mediated via RAR alpha, because (1 ) it can be reproduced by various RAR alpha analogues both in vitro an d in vivo, (2) the effect of RAs can be inhibited by the addition of a n RAR alpha antagonist, (3) CD4+CD8+thymocytes, which die on TCR stimu lation, express RAR alpha. Stimulation of RAR gamma, in contrast, enha nces the activation-induced death of thymocytes and inhibits its preve ntion by RAR alpha stimulation. RXR co-stimulation suspends this inhib itory effect of RAR gamma and permits the preventive function of RAR a lpha on activation-induced death. Our results suggest a complex intera ction between the various isoforms of retinoid receptors and demonstra te that low (physiological) concentrations of all-trans-RA do not affe ct the activation-induced death of thymocytes because the RAR alpha-me diated inhibitory and the RAR gamma-mediated enhancing pathways are in balance, whereas if 9-cis-RA is formed, additional stimulation of RXR s permits the inhibitory action of RAR alpha.