The effects of interleukin-2 treatment on endothelin and the activation of the hypothalamic–pituitary–adrenal axis

OBJECTIVE: Recent reports suggest that complex interactions exist between the neuroendocrine and immune systems. It has been shown for example that cytokines are able to stimulate the hypothalamo-pituitary-adrenal axis. In addition, some studies present evidence that endothelin is able to modulate the activity of several hypothalamic-pituitary axes, e.g. by inducing the ACTH production. DESIGN: We investigated the effects of interleukin-2 on endothelin levels and the hypothalamo-pituitary-adrenal axis. We determined the interleukin-6, big-endothelin, endothelin-1, ACTH, cortisol and AVP responses to intravenously and subcutaneously administered interleukin-2 in 8 cancer patients in a randomized placebo controlled trial. PATIENTS: 8 Patients (2 female and 6 male), age 44 +/- 4.8 years, were enrolled. All patients had a World Health Organization performance status of 1 or less and a Karnofsky Index of at least 80%. MEASUREMENTS: Blood-samples were taken before and 15, 30, 45, 60, 120, 180, 240, 300 and 360 min after interleukin-2 injection. Cytokine serum levels and the plasma levels of big-endothelin, endothelin, ACTH and AVP were analysed using radioimmuno-assays. Cortisol was assayed by an enzyme-linked immunosorbent assay. RESULTS: Interleukin-2 treatment significantly increased plasma big-endothelin levels (P < 0.01 vs basal) and endothelin-1 levels (P < 0.05 vs basal) within two hours and this was followed by an increase in ACTH (P < 0.01 vs basal) and cortisol (P < 0.05 vs basal) within three hours. Interleukin-6 levels increased two hours after interleukin-2 administration (P < 0.01 vs basal). Interleukin-2 had no detectable effect on AVP, blood pressure or heart rate. CONCLUSIONS: Our data demonstrate that cytokines are able to activate the human hypothalamo-pituitary-adrenal axis in vivo. On the basis of the observed time kinetics and in connection with previous findings from in vitro and animal models, we conclude that endothelin may be a link between cytokines and corticotrophin-releasing hormone, most probably functioning as a cytokine-induced neuromodulator controlling pituitary functions.