Elevated glutathione S‐transferase gene expression is an early event during steroid‐induced lymphocyte apoptosis

Based on the finding that glutathione S‐transferase Yb₁ (GST) gene expression is elevated in the regressing prostate of androgen‐ablated rats, we analyzed GST transcript levels during steroid‐induced lymphocyte cell death. It was found that GST gene expression was induced in steroid‐sensitive cells within 4 hr of dexamethasone treatment, required functional glucocorticoid receptor, and was dose‐dependent with regard to hormone. GST expression was not induced in an apoptosis‐defective variant that contained normal levels of functional receptor, indicating that GST up‐regulation was the result of secondary events that occur during steroid‐mediated apoptosis. Using the calcium ionophore A23817 to induce lymphocyte cell death, GST RNA levels were increased in both steroid‐sensitive and steroid‐resistant cell lines, supporting the conclusion that elevated GST expression was the result of cellular processes associated with apoptosis, rather than a direct consequence of steroid‐mediated transcriptional control. The cells were also treated with dibutyryl cAMP to cause cell death; however, this mode of killing did not result in GST up‐regulation. Taken together, these results suggest that GST induction in dexamethasone‐treated T‐lymphocytes occurs early in the steroid‐regulated apoptotic pathway and that this may be a marker of calcium‐stimulated cell death. Based on the known function of GST as an antioxidant defense enzyme and its transcriptional regulation by reactive oxygen intermediates, we propose that the gene product of a primary GR target gene(s) directly or indirectly effects the redox state of the cell. Thus activation of GST gene expression in apoptotic lymphocytes is likely a indicator of oxidative stress, rather than a required step in the pathway. © 1993 Wiley‐Liss, Inc.