The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.