RAR, NOT RXR, LIGANDS INHIBIT CELL ACTIVATION AND PREVENT APOPTOSIS IN B-LYMPHOCYTES

We have previously shown that retinoids inhibit activation of human pe ripheral blood B-lymphocytes. In the present paper, we wished to explo re the involvement of nuclear retinoid-specific receptors in this proc ess by using ligands specific for the retinoic acid receptors (RARs) a nd retinoid X receptors (RXRs). We found that the RAR-specific ligand TTAB reduced anti-IgM-induced B-cell activation in a dose-dependent ma nner. Thus, at 100 nM of TTAB, DNA synthesis was reduced by approximat ely 60%. In contrast, the RXR-selective ligand SR11217 had no effect o n DNA synthesis. Similar findings were obtained when the expression of the activation antigen CD71 (appears late in G1) was examined. The ro le of retinoids in apoptosis of resting peripheral blood B-lymphocytes was examined using the same receptor-selective ligands. Again, we fou nd that the RAR-selective ligands were more potent effecters than were the RXR-selective ligands. In spite of the inhibitory effects of reti noids on B-cell proliferation, the same retinoids significantly promot ed the survival of the cells. Thus, 10 nM TTAB significantly reduced s pontaneous apoptosis of in vitro cultured B-cells at day 3 from 45% to 30%, as determined by vital dye staining and DNA end-labeling. Again, the RXR-specific ligand SR11217 had no effect. Interestingly, we foun d that CD40 ligand was able to potentiate the retinoid-mediated inhibi tion of apoptosis. By reverse transcriptase polymerase chain reaction (PCR), we found that peripheral blood B-lymphocytes expressed RAR alph a, RAR gamma, and RXR alpha, but not RAR beta, RXR beta, or RXR gamma. Hence, the lack of effect of the RXR-specific ligand SR11217 on growt h and apoptosis was not due to absence of RXRs. In conclusion, the abi lity of retinoids to inhibit growth and prevent apoptosis of normal hu man B-lymphocytes indicates a dual role of retinoids in this cell comp artment, and it appears that both effects of retinoids are mediated vi a RARs and not RXRs. (C) 1998 Wiley-Liss, Inc.