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

J Clin Endocrinol Metab. 1993 Dec;77(6):1690-4. doi: 10.1210/jcem.77.6.8263159.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • 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


  • Interleukin-6
  • Recombinant Proteins
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Hydrocortisone