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) str ongly stimulates the human hypothalamic-pituitary-adrenal (HPA) axis, with mild toxicity and no hypotensive effects. In this study, we evalu ated the response of the human HPA axis to escalating iv doses of reco mbinant IL-6 in six patients with cancer and good performance status w ho received daily, every 8 h, three equal doses of 0.3-30 mu g/kg IL-6 . The plasma levels of IL-6 assayed by a specific enzyme-linked immuno sorbent assay during the 4 h following the first IL-6 injection were e levated for 2-4 h, proportionally to the amount of injected IL-6. Admi nistration 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) independen tly of the IL-6 dose administered, suggesting that the doses employed were at the tap of the dose-response curve for these hormones. Interes tingly, plasma arginine vasopressin (AVP) levels were also elevated du ring the 2 h after IL-6 injection in all patients who received a dose of 3 mu g/kg or more, suggesting that IL-6 activated the magnocellular AVP-secreting neurons and that it might be involved in the syndrome o f 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, su ggesting that there was no rapid tachyphylaxis in response to IL-6 adm inistration. Plasma IL-1 beta and tumor necrosis factor-alpha concentr ations, 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 o f the human HPA axis and a secretagogue of magnocellular AVP secretion , which might be employed as a challenge test of the axis and the magn ocellular AVP neuron.