Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.
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.
Mastorakos
G
G
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Chrousos
G P
GP
Weber
J S
JS
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology
D015850:Interleukin-6; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone