9-cis Retinoic Acid Inhibition of Activation-Induced Apoptosis Is Mediated via Regulation of Fas Ligand and Requires Retinoic Acid Receptor and Retinoid X Receptor Activation

Abstract

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.

Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

“…9). All-trans-RA is known to mediate its response through RAR (24), and TTNPB, a synthetic retinoid analog, acts as a selective RAR agonist (25). Both the all-trans-RA-and TTNPB-mediated increases in SCD mRNA expression were effectively blocked by AGN194301, a RAR␣-specific antagonist (26).…”

“…TTNPB is a synthetic, highly selective RAR agonist with no affinity for RXR (25). TTNPB induced SCD expression, and the induction was blocked completely by AGN194301, an RAR␣ antagonist.…”

Involvement of 5-lipoxygenase in programmed cell death of cancer cells

“…Although the nucleus plays a central role in PCD, cellular membranes are the primary site of action of several PCD inducers and lipid messengers act as regulators of apoptosis (Bissonnette et al, 1995;McGahon et al, 1995). 5-Lipoxygenase (EC 1.13.11.34) plays a critical role in lipidmediated signal transduction (Los et al, 1995) and its metabolites were recently found to be active in the nucleus of human cells (Jakobsson et al, 1995).…”

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

“…First, retinoids are known to regulate apoptosis in T lymphocytes, thymocytes, and T lymphoma cells (7,21,44). Second, in addition to promoting Th2 development, treatment with the RXR agonist AGN194204 during primary antigenic stimulation reproducibly caused a greater accumulation of viable cells after 1 wk of culture than did treatment with the vehicle control.…”