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.
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.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
G
G
Mastorakos
J S
JS
Weber
M A
MA
Magiakou
H
H
Gunn
G P
GP
Chrousos
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001127:Arginine Vasopressin / Q000097:blood / Q000378:metabolism*; D002940:Circadian Rhythm; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007177:Inappropriate ADH Syndrome / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
D016207:Cytokines; D015850:Interleukin-6; D011994:Recombinant Proteins; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone