Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase

Interferons (IFNs) and retinoids are potent biological response modifiers. The IFN-beta and all-trans-retinoic acid combination, but not these single agents individually, induces death in several tumor cell lines. To elucidat e the molecular basis for these actions, we have employed an antisense knoc kout approach to identify the gene products that mediate cell death and iso lated several genes associated with retinoid-IFN-induced mortality (GRIMs), One of the GRIM cDNAs, GRIM-12, was identical to human thioredoxin reducta se (TR). To define the functional relevance of TR to cell death and to defi ne its mechanism of death-modulating functions, we generated mutants of TR and studied their influence on the IFN/RA-induced death regulatory function s of caspases, Wild-type TR activates cell death that was inhibited in the presence of caspase inhibitors or catalytically inactive caspases, A mutant TR, lacking the active site cysteines, inhibits the cell death induced by caspase 8. IFN/all-trans-retinoic acid-induced cytochrome c release from th e mitochondrion was promoted in the presence of wild type and was inhibited in the presence of mutant TR, We find that TR modulates the activity of ca spase 8 to promote death. This effect is in part caused by the stimulation of death receptor gene expression. These studies identify a new mechanism o f cell death regulation by the IFN/all-trans-retinoic acid combination invo lving redox enzymes.