Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans

• Published in: The journal of clinical endocrinology and metabolism Vol. 77; no. 6; p. 1690
• Main Authors: Mastorakos, G, Chrousos, G P, Weber, J S
• Format: Journal Article
• Language: English
• Published: United States 01.12.1993
• Subjects: Adrenocorticotropic Hormone - blood; Adult; Aged; Corticotropin-Releasing Hormone - blood; Corticotropin-Releasing Hormone - pharmacology; Female; Humans; Hydrocortisone - blood; Hypothalamo-Hypophyseal System - drug effects; Interleukin-6 - pharmacology; Male; Middle Aged; Pituitary-Adrenal System - drug effects; Recombinant Proteins - pharmacology
• ISSN: 0021-972X
• DOI: 10.1210/jc.77.6.1690

The inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha and -beta (IL-1 alpha and -beta), and IL-6 can activate the hypothalamic-pituitary-adrenal (HPA) axis. Tumor necrosis factor-alpha and IL-1 have been tested in both experimental animals and humans, but their administration has been limited by significant toxicity, mainly severe hypotension. IL-6, on the other hand, has demonstrated modest toxicity in animals. We evaluated the ability of recombinant IL-6 to stimulate the human HPA axis in patients with cancer and a good performance status, who received daily morning sc injections of 30 micrograms/kg IL-6 for 7 consecutive days, during the course of a phase I trial. IL-6 caused impressively marked and prolonged elevations of plasma ACTH and cortisol on the first day and blunted ACTH responses on the seventh day of treatment, perhaps as a result of increased baseline cortisol levels. The overall cortisol response, however, on the seventh day was of similar magnitude, suggesting that a new equilibrium in the feedback regulation of the HPA axis occurs with chronic IL-6 administration. The toxic effects of IL-6 were modest, suggesting that it might be useful for clinical testing of the HPA axis, as an alternative to the insulin tolerance test.