EXERCISE AND CIRCADIAN RHYTHM-INDUCED VARIATIONS IN PLASMA-CORTISOL DIFFERENTIALLY REGULATE INTERLEUKIN-1-BETA (IL-1-BETA), IL-6, AND TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) PRODUCTION IN HUMANS - HIGH-SENSITIVITY OF TNF-ALPHA AND RESISTANCE OF IL-6

Although we have previously shown that the integrity of inflammatory m ediator-induced activation of the hypothalamic-pituitary-adrenal axis is essential for conferring resistance to inflammatory disease in susc eptible Lewis rats, the role of endogenous glucocorticoid secretion in human immune function in either health or disease is less clear. To f urther understand the relevance of physiological variations in plasma cortisol on immune function in humans, we evaluated ex vivo lipopolysa ccharide-induced interleukin-1 beta (IL-1 beta) IL-6, and tumor necros is factor-alpha (TNF alpha) production in the whole blood of healthy v olunteers studied under conditions chosen to approximate either physio logical or pharmacological glucocorticoid levels. Administration of a pharmacological dose of hydrocortisone suppressed the production of al l three cytokines, whereas administration of a physiological dose of h ydrocortisone suppressed only TNF alpha production. Stress-induced lev els of glucocorticoids, achieved during exercise at 100% maximal oxyge n utilization, suppressed IL-1 beta and TNF alpha production, but were without effect on IL-6 production. In addition, circadian variations of cortisol were associated with decreased TNF alpha production, but w ere without effect on IL-1 beta or IL-6 production. These studies chal lenge the generally accepted idea that glucocorticoids consistently su ppress cytokine production and indicate a hierarchy of sensitivity, wi th TNF alpha having the greatest sensitivity, IL-1 beta having interme diate sensitivity, and IL-6 being resistant. The resistance of IL-6 pr oduction to glucocorticoid suppression is compatible with data suggest ing an antiinflammatory as well as a proinflammatory action for this c ytokine.