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Retinoic acid regulates Fas‐induced apoptosis in Jurkat T cells: reversal of mitogen‐mediated repression of Fas DISC assembly
Author(s) -
Engedal Nikolai,
Auberger Patrick,
Blomhoff Heidi Kiil
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1107790
Subject(s) - apoptosis , jurkat cells , programmed cell death , biology , mapk/erk pathway , microbiology and biotechnology , dna fragmentation , retinoic acid , fas ligand , apoptotic dna fragmentation , ripk1 , fas receptor , signal transduction , cell culture , t cell , immunology , immune system , biochemistry , necroptosis , genetics
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 μM, repression of Fas‐induced cell death by the mitogens 12‐ O ‐tetradecanoylphorbol 13‐acetate (TPA) or Con A was reversed by ∼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‐κB. However, analyses of ERK and NF‐κB 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‐κB 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.