Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor- mediated transcription

Zsuzsa Szondy (1) , Katalin Toth (1) , Zsolt Sarang (1) , Beata Scholtz (1) , Laszlo Fesus (1) , Peter Brazda (1) , Norbert B. Ghyselinck (1) , Pierre Chambon (1)

1 Biochemistry and Molecular Biology

Glucocorticoid-induced apoptosis of thymocytes is one of the first recognized forms of programmed cell death. It was shown to require gene activation induced by the glucocorticoid receptor (GR) translocated into the nucleus following ligand binding. In addition, the necessity of the glucocorticoid-induced, but transcription-independent phosphorylation of phosphatidylinositol-specific phospholipase C (PI-PLC) has also been demonstrated. Here we report that retinoic acids, physiological ligands for the nuclear retinoid receptors, enhance glucocorticoid-induced death of mouse thymocytes both in vitro and in vivo. The effect is mediated via retinoic acid receptor (RAR) alpha/retinoid X receptor (RXR) heterodimers, and occurs when both RARα and RXR are ligated by retinoic acids. We demonstrate that the ligated RARα/RXR interacts with the ligated GR resulting in an enhanced transcriptional activity of the GR. The mechanism through which this interaction promotes GR-mediated transcription does not require DNA binding of the retinoid receptors and does not alter the phosphorylation status of Ser212, known to regulate the transcriptional activity of GR. Phosphorylation of PI-PLC was not affected. Besides thymocytes, retinoids also promoted glucocorticoid-induced apoptosis of various T cell lines suggesting that they could be used in the therapy of glucocorticoid sensitive T cell malignancies.

Mots clés: apoptosis; glucocorticoid; retinoid; T cells

Zsuzsa Szondy, Katalin Toth, Zsolt Sarang, Beata Scholtz, Laszlo Fesus, et al.. Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor- mediated transcription. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.136⟩. ⟨hal-00592290⟩