REGULATION OF CYTOKINE GENE-EXPRESSION IN THE CENTRAL-NERVOUS-SYSTEM BY GLUCOCORTICOIDS - MECHANISMS AND FUNCTIONAL CONSEQUENCES

The proinflammatory cytokines which are released by activated accessor y immune cells during the course of an infection have profound effects on the brain. These effects include activation of the hypothalamic-pi tuitary-adrenal axis, fever and behavioral depression. They are mediat ed by cytokines which are synthesized and released in the brain, in re sponse to peripherally released cytokines. Glucocorticoids have potent regulatory effects on the synthesis of cytokines by activated macroph ages and monocytes. These hormones are also able to regulate the synth esis and action of cytokines in the brain, as demonstrated by the sens itizing effects of adrenalectomy and the depressing effects of stress on the increased cytokine and interleukin-1 beta converting enzyme gen e expression that occurs in response to lipopolysaccharide in mice. Pr eliminary experiments indicate that another way glucocorticoids can co ntribute to down regulation of the IL-1 system is by increasing the ex pression of the type II IL-I receptor in the brain. The regulatory eff ects of glucocorticoids on cytokine expression in the brain have funct ional consequences, as demonstrated by the enhanced sensitivity of adr enalectomized animals to the behavioral actions of centrally administe red LPS and IL-l. The effects of adrenalectomy are inhibited by compen sation with a corticosterone implant and they are mimicked by administ ration of the type II glucocorticoid receptor, RU 38486. The regulator y role of glucocorticoids on the expression and action of cytokines in the brain makes these hormones and their mechanisms of action key tar gets for therapeutic interventions in psychopathology and neuropatholo gy. (C) 1997 Elsevier Science Ltd.