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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2182-2191
Copyright © 1997 by The Endocrine Society

Clinical Studies

Exercise and Circadian Rhythm-Induced Variations in Plasma Cortisol Differentially Regulate Interleukin-1ß (IL-1ß), IL-6, and Tumor Necrosis Factor-{alpha} (TNF{alpha}) Production in Humans: High Sensitivity of TNF{alpha} and Resistance of IL-6

Roel DeRijk, David Michelson, Brian Karp, John Petrides, Elise Galliven, Patty Deuster, Giulio Paciotti, Philip W. Gold and Esther M. Sternberg

Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health (R.D., D.M., B.K., E.S., P.G.), Bethesda, Maryland 20892; the Departments of Physiology and Military and Emergency Medicine, Uniformed Services of the University of the Health Sciences,(J.P., E.G., P.D.), Bethesda, Maryland 20814; and CytImmune Sciences Inc. (G.P.), College Park, Maryland 20740

Address all correspondence and requests for reprints to: Dr. R. H. DeRijk, Leiden/Amsterdam Center for Drug Research, Center for Bio-Pharmaceutical Sciences, Sylvius Laboratories, Wassenaarseweg 72, 2300 RA Leiden, The Netherlands. E-mail: r.rijk{at}lacdr.leidenuniv.nl

Although we have previously shown that the integrity of inflammatory mediator-induced activation of the hypothalamic-pituitary-adrenal axis is essential for conferring resistance to inflammatory disease in susceptible Lewis rats, the role of endogenous glucocorticoid secretion in human immune function in either health or disease is less clear. To further understand the relevance of physiological variations in plasma cortisol on immune function in humans, we evaluated ex vivo lipopolysaccharide-induced interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-{alpha} (TNF{alpha}) production in the whole blood of healthy volunteers studied under conditions chosen to approximate either physiological or pharmacological glucocorticoid levels.

Administration of a pharmacological dose of hydrocortisone suppressed the production of all three cytokines, whereas administration of a physiological dose of hydrocortisone suppressed only TNF{alpha} production. Stress-induced levels of glucocorticoids, achieved during exercise at 100% maximal oxygen utilization, suppressed IL-1ß 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 were without effect on IL-1ß or IL-6 production.

These studies challenge the generally accepted idea that glucocorticoids consistently suppress cytokine production and indicate a hierarchy of sensitivity, with TNF{alpha} having the greatest sensitivity, IL-1ß having intermediate sensitivity, and IL-6 being resistant. The resistance of IL-6 production to glucocorticoid suppression is compatible with data suggesting an antiinflammatory as well as a proinflammatory action for this cytokine.




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