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.

Abstract

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.

Hyponatremia in visceral leishmaniasis

“…The widespread and intensive inflammatory state involving the lungs, the liver, the kidneys, the intestines and the lymphatic ganglia induced to increase production of plasma prostaglandins and renin 9,29,33,34 . High serum levels of interleukin-6 have been detected in visceral leishmaniasis 3,32 and can act as a potent stimulus of the hypothalamicpituitary-adrenal axis and to arginine vasopressin(ADH) release too 14,22 .…”

Ticks and salt: an atypical case of neuroborreliosis

“…The relationship between intracranial inflammation and ADH may be from increased levels of pro-inflammatory cytokines (i.e., IL-6, IL-1B), as well as of neutrophils, C-reactive protein and brain natriuretic peptide, all leading to increased release of ADH. A very small study done in 1994 including six patients with cancer showed that two hours after injection with IL-6, plasma ADH rose in all patients suggesting that this inflammatory cytokine may directly cause SIADH [15]. When inflammatory processes are responsible for SIADH, the syndrome usually will resolve after treatment of the infection [16,17].…”

Organization and Integration of the Endocrine System: The Arousal and Sleep Perspective

“…Thus, in humans, IL-6 is an extremely potent activator of the axis and lacks the vascular leak-promoting and hypotensive side effects of the other two inflammatory cytokines. [110,111] The elevations in ACTH and cortisol levels attained by IL-6 are well above those observed with maximal stimulatory doses of CRH, suggesting that parvocellular AVP and other ACTH secretagogues are also recruited by this cytokine. At high doses, IL-6 also stimulates peripheral elevations of AVP, presumably as a result of a stimulatory effect on magnocellular AVP-secreting neurons.…”

“…At high doses, IL-6 also stimulates peripheral elevations of AVP, presumably as a result of a stimulatory effect on magnocellular AVP-secreting neurons. [111] This suggests that IL-6 may be involved in the genesis of the syndrome of inappropriate antidiuretic hormone secretion, which is observed during the course of infectious or inflammatory disease or during trauma.…”

“…[125] Despite its inherent inflammatory activity, IL-6, by causing glucocorticoid secretion [110][111] and by directly suppressing the secretion of tumor necrosis factor-a and IL-1, [105] plays a major role in the overall control of inflammation.…”