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 approximately 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 upregulation and T cell apoptosis by retinoic acid.
Yang
Y
Y
Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, MD 20892-1152, USA.
Minucci
S
S
Ozato
K
K
Heyman
R A
RA
Ashwell
J D
JD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017252:CD3 Complex / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D017930:Genes, Reporter; D006825:Hybridomas / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors