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 and Inflammation: The Emerging Role of Interleukin-6 in Osmoregulation

“…LPS-induced vasopressin release was shown to be independent of known stimuli, including serum osmolality, and hemodynamic changes [15]. Interestingly, vasopressin secretion was also stimulated by intravenous injection of IL-1β in rats [16], by intracerebroventricular injection of IL-6 in rats [17] and, most notably, by intravenous injection of IL-6 in humans [18]. Similarly, oxytocin secretion was stimulated by the administration of LPS or IL-1β [19].…”

“…Mastorakos et al [18] showed that in these patients the administration of IL-6 resulted in a fast dose-dependent rise in vasopressin concentration (to 15.6 pg/ml, normal range ∼1–4 pg/ml). Importantly, IL-6 treatment did not influence TNF-α or IL-1β concentrations, suggesting that vasopressin release by IL-6 can occur independently of its associated cytokines.…”

Pediatric Stress: Hormonal Mediators and Human Development

“…Despite its inherent inflammatory activity, IL-6 plays a major role in the overall control of inflammation, by stimulating glucocorticoid secretion [83, 84]and by suppressing the secretion of TNF-α and IL-1. Furthermore, catecholamines inhibit IL-12 and stimulate IL-10 secretion via β-adrenergic receptors, thereby causing suppression of innate and cellular immunity, and stimulation of humoral immunity [85].…”

Interleukin-12 p40 Gene Expression Is Induced in Lipopolysaccharide-Activated Pituitary Glands in vivo

“…Activation of the HPA axis by proinflammatory cytokines provokes the release of glucocorticoids which, in turn, prevent the continuing immune-inflammatory response [1]and thereby regulates a homeostatic neuroendocrine-immune regulatory loop. For example, proinflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α), are expressed in HPA axis tissues [2, 3, 4]and stimulate the release of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and corticosterone [5, 6, 7, 8, 9, 10]. This indicates that proinflammatory cytokines play an important role in maintaining neuroendocrine-immune homeostasis through the HPA axis.…”