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

OBJECTIVE Recent reports suggest that complex interactions exist between th e neuroendocrine and immune systems, It has been shown for example that cyt okines are able to stimulate the hypothalamopituitary-adrenal axis, In addi tion, 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 an d the hypothalamo-pituitary-adrenal axis. We determined the interleukin-6, big-endothelin, endothelin-1, ACTH, cortisol and AVP responses to intraveno usly 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 enrol led. All patients had a World Health Organization performance status of 1 o r less and a Karnofsky Index of at least 80%, MEASURMENTS Blood-samples wer e taken before and 15, 30, 45, 60, 120, 180, 240, 300 and 360 min after int erleukin-1 injection. Cytokine serum levels and the plasma levels of big-en dothelin, endothelin, ACTH and AVP were analysed using radioimmunoassays. C ortisol was assayed by an enzyme-linked immunosorbent assay, RESULTS Interleukin-2 treatment significantly increased plasma big-endothel in levels (P < 0.01 vs basal) and endothelin-l levels (P < 0.05 vs basal) w ithin two hours and this was followed by an increase in ACTH (P < 0.01 vs b asal) and cortisol (P < 0.05 vs basal) within three hours. Interleukin-6 le vels increased two hours after interleukin-2 administration (P < 0.01 vs ba sal). Interleukin-2 had no detectable effect on AVP, blood pressure or hear t rate. CONCLUSIONS Our data demonstrate that cytokines are able to activate the hu man hypothalamo-pituitary-adrenal axis in vivo. On the basis of the observe d 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 cytoki ne-induced neuromodulator controlling pituitary functions.