Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression.

Our data indicate that the proinflammatory cytokine, IL-1alpha inhibits GR translocation and hormone-induced GR-mediated gene transcription, and, in conjunction with previous in vivo and in vitro studies, can be interpreted to suggest that cytokines have the capacity to contribute to glucocorticoid resistance and thus the pathophysiology of depression. In addition, data from our mouse viral studies in glucocorticoid deficient animals demonstrate that endogenous glucocorticoids modulate a delicate balance between viral defense and cytokine toxicity. Finally, the antidepressant, DMI, has been found to enhance GR translocation and GR-mediated gene transcription and thus may provide a useful strategy for adjusting neuroendocrine setpoints in vivo. Taken together, these findings suggest that factors which modulate glucocorticoid action (e.g. cytokines and antidepressants) will be relevant contributors to disease expression including behavioral toxicity and sickness behavior.