In experimental animals, stress and catecholamines stimulate endogenous interleukin-6 (IL-6) secretion, whereas glucocorticoids inhibit it. To examine whether physical stress alters the secretion of IL-6 in humans, and to what extent this is correlated with catecholamines and modified by glucocorticoids, we performed high-intensity treadmill exercise test runs on 15 male volunteers, in a double-blind crossover design, after pretreatment with placebo, hydrocortisone, or dexamethasone. Plasma epinephrine and norepinephrine concentrations peaked 15 min after the start of exercise, whereas plasma IL-6 concentrations peaked twice, 15 min and 45 min after the onset of the test run. There was no difference in either the epinephrine or norepinephrine peaks among the three treatments, but the net area under the curve for IL-6 was smaller after hydrocortisone or dexamethasone than after placebo and smaller after dexamethasone than after hydrocortisone. A positive correlation was observed between peak plasma epinephrine or norepinephrine and IL-6 levels at 15 min. These findings suggest that IL-6 secretion is stimulated during exercise, possibly by catecholamines, whereas exogenous glucocorticoids attenuate this effect without affecting the catecholamine levels.
To compare profiles of hypothalamic-pituitary-adrenal (HPA) responsiveness, healthy, moderately trained men (n = 15) were classified as high (n = 7) or low responders (n = 8) on the basis of plasma adrenocorticotropic hormone (ACTH) responses to strenuous treadmill exercise 4 h after 4 mg of dexamethasone (Dex). These groups were then evaluated to compare 1) HPA and growth hormone responses to exercise at 90% maximal oxygen uptake 4 h after placebo, Dex (4 mg), and hydrocortisone (100 mg); 2) pituitary-adrenal responses to infusion of arginine vasopressin (AVP); 3) plasma cortisol after a Dex suppression test (1 mg); and 4) behavioral characteristics. In comparison to low responders, high responders exhibited significantly 1) higher plasma ACTH responses to exercise after placebo and Dex; 2) higher plasma AVP secretion with exercise after placebo and marked Dex- and hydrocortisone-induced enhancement of exercise-induced AVP secretion; 3) lower Dex-induced increases in basal and stimulated growth hormone secretion; 4) higher plasma ACTH responses to infusion of AVP; and 5) a trend (P = 0.09) for higher trait anxiety ratings. Similar suppression of plasma cortisol was noted after 1 mg Dex. We conclude that subgroups of healthy male volunteers exhibit unique profiles of HPA responsiveness. We also believe that glucocorticoid pretreatment combined with strenuous exercise allows functional HPA responsiveness to be distinguished between subgroups of healthy controls and may be useful in the determination of susceptibility to disorders characterized by hyper- and hypo-HPA activation.
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-1 beta (IL-1 beta), 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-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 were without effect on IL-1 beta 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-1 beta 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.
Treadmill exercise activates the hypothalamic-pituitary-adrenal axis and evokes metabolic responses proportional to exercise intensity and duration. To determine whether glucocorticoid administration would alter humoral and metabolic regulation during exercise, we administered 4 mg dexamethasone (DEX) or placebo to 11 normal, moderately trained men (19-42 yr old) in a double blinded random fashion 4 h before high intensity intermittent treadmill running. Plasma levels of ACTH, cortisol, arginine vasopressin (AVP), lactate, and glucose were measured before, during, and after exercise. A wide range of ACTH responses were seen in the DEX-treated group and arbitrarily defined as two subsets of individuals according to their responses to dexamethasone: DEX nonsuppressors and DEX suppressors. Exercise-induced increases in heart rate and circulating concentrations of cortisol, AVP, lactate, and glucose were all significantly greater (P < 0.05) in nonsuppressors (n = 4) compared to suppressors (n = 7) after both placebo and DEX administration. Interestingly, heart rate, AVP, and lactate responses were unaltered by DEX alone in both groups. In summary, this study demonstrates that normal individuals exhibit differential neuroendocrine and metabolic responses to exercise and pituitary/adrenal suppression after pretreatment with DEX. These findings reflect marked individual differences in the stress response to exercise that may derive from or lead to differential glucocorticoid negative feedback sensitivity in humans.
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