Thioredoxin in the endocrine response to stress

Adaptation to stress evokes a variety of biological responses, including activation of the hypothalamic--pituitary--adrenal (HPA) axis and synthesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced under oxidative conditions. Glucocorticoids, as a peripheral effector of the HPA axis, exert their action via interaction with a ligand-inducible transcription factor glucocorticoid receptor (GR). However, how these stress responses coordinately regulate cellular metabolism is still unknown. We demonstrate that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most probably through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX. Together, we propose that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level, suggesting that cross-talk between neuro-endocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.