Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly

Print
Published on Thursday, 06 November 2014

Abstract

The effect of the immune regulator vitamin A on T cell death has been poorly characterized.

In the present study, we demonstrate that an active metabolite of vitamin A, retinoic acid (RA), promotes cell death in Jurkat leukemic T cells by counteracting mitogen-mediated repression of Fas-induced apoptosis.

The effect of RA was dose-dependent, and at the optimal concentration of 1 muM, repression of Fas-induced cell death by the mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) or Con A was reversed by approximately 50% and 30%, respectively.

RA promoted apoptosis rather than necrosis, as judged by analysis of cell morphology, mitochondrial membrane depolarization, and DNA fragmentation.

TPA-mediated protection from Fas-induced apoptosis is dependent on ERK and NF-kappaB. However, analyses of ERK and NF-kappaB activities and expression of target genes indicated that RA-mediated counteraction of the protective effect of TPA did not involve negative crosstalk with ERK or NF-kappaB survival pathways.

RA-induced cell death was accompanied by enhanced cleavage of procaspase-3, -6, and -8, as well as enhanced cleavage of DNA fragmentation factor 45. Interestingly, RA-mediated cleavage of procaspase-8 occurred very early and before any effect of RA could be detected on procaspase-3 cleavage, suggesting that RA might act at the level of the Fas death-inducing signaling complex (DISC).

Indeed, DISC immunoprecipitation studies revealed that RA treatment reversed the inhibitory effect of TPA on CH11-induced recruitment and processing of procaspase-8 at the DISC.

In conclusion, we have identified a role of RA in abrogating mitogen-mediated repression of Fas DISC assembly, thus enhancing Fas-induced apoptosis in leukemic T cells.

 



Download the complete article

 

About this publication.

 

See also All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives).