Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion

J Clin Endocrinol Metab. 1994 Oct;79(4):934-9. doi: 10.1210/jcem.79.4.7962300.


We recently demonstrated that sc administered interleukin-6 (IL-6) strongly stimulates the human hypothalamic-pituitary-adrenal (HPA) axis, with mild toxicity and no hypotensive effects. In this study, we evaluated the response of the human HPA axis to escalating iv doses of recombinant IL-6 in six patients with cancer and good performance status who received daily, every 8 h, three equal doses of 0.3-30 micrograms/kg IL-6. The plasma levels of IL-6 assayed by a specific enzyme-linked immunosorbent assay during the 4 h following the first IL-6 injection were elevated for 2-4 h, proportionally to the amount of injected IL-6. Administration of the cytokine was followed by marked elevations of plasma ACTH (53.0-98.6 pmol/L) and cortisol (824.9-1729.9 nmol/L) independently of the IL-6 dose administered, suggesting that the doses employed were at the top of the dose-response curve for these hormones. Interestingly, plasma arginine vasopressin (AVP) levels were also elevated during the 2 h after IL-6 injection in all patients who received a dose of 3 micrograms/kg or more, suggesting that IL-6 activated the magnocellular AVP-secreting neurons and that it might be involved in the syndrome of inappropriate AVP secretion. Cortisol elevations with peaks similar to those observed after the first injection of IL-6 were also detected in plasma sampled every 2 h after the second and third injections, suggesting that there was no rapid tachyphylaxis in response to IL-6 administration. Plasma IL-1 beta and tumor necrosis factor-alpha concentrations, assayed by specific enzyme-linked immunosorbent assays during the 4 h after the first IL-6 injection, were either within the normal range or undetectable, confirming in vitro observations that IL-6 does not stimulate IL-1 beta or tumor necrosis factor-alpha secretion and suggesting that it exerts its effect on the HPA axis and AVP secretion independently of them. We conclude that IL-6 is a potent stimulator of the human HPA axis and a secretagogue of magnocellular AVP secretion, which might be employed as a challenge test of the axis and the magnocellular AVP neuron.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Arginine Vasopressin / blood
  • Arginine Vasopressin / metabolism*
  • Circadian Rhythm
  • Corticotropin-Releasing Hormone / blood
  • Cytokines / blood
  • Female
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiology*
  • Inappropriate ADH Syndrome / metabolism*
  • Interleukin-6 / pharmacology*
  • Male
  • Middle Aged
  • Recombinant Proteins


  • Cytokines
  • Interleukin-6
  • Recombinant Proteins
  • Arginine Vasopressin
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Hydrocortisone