Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL-6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 micrograms/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 h after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-microgram/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-microgram/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 h. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 micrograms/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 micrograms/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.