THIOREDOXIN - A REDOX-REGULATING CELLULAR COFACTOR FOR GLUCOCORTICOIDHORMONE ACTION - CROSS-TALK BETWEEN ENDOCRINE CONTROL OF STRESS-RESPONSE AND CELLULAR ANTIOXIDANT DEFENSE SYSTEM

Adaptation to stress evokes a variety of biological responses, includi ng activation of the hypothalamic-pituitary-adrenal (HPA) axis and syn thesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced unde r oxidative conditions. Glucocorticoids, as a peripheral effector of t he HPA axis, exert their actions via interaction with a ligand-inducib le transcription factor glucocorticoid receptor (GR). However, how the se stress responses coordinately regulate cellular metabolism is still unknown. In this study, we demonstrated that either antisense TRX exp ression or cellular treatment with H2O2 negatively modulates GR functi on and decreases glucocorticoid-inducible gene expression. Impaired ce llular response to glucocorticoids is rescued by overexpression of TRX , most possibly through the functional replenishment of the GR. Moreov er, not only the ligand binding domain but the DNA binding domain of t he GR is also suggested to be a direct target of TRX. Together, we her e present evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and propose th at cross talk between neuroendocrine control of stress responses and c ellular antioxidant systems may be essential for mammalian adaptation processes.