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.


METHODS
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.


METHODS
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%.


METHODS
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.
Raab
C
C
Medical Department I, Johann Wolfgang Goethe-University, Frankfurt, Germany.
Weidmann
E
E
Schmidt
A
A
Bergmann
L
L
Badenhoop
K
K
Usadel
K H
KH
Haak
T
T
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001127:Arginine Vasopressin / Q000097:blood; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007376:Interleukin-2 / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007680:Kidney Neoplasms / Q000097:blood / Q000628:therapy; D008297:Male; D008545:Melanoma / Q000097:blood / Q000628:therapy; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000628:therapy; D011498:Protein Precursors / Q000097:blood; D013268:Stimulation, Chemical
D019332:Endothelin-1; D016232:Endothelins; D007376:Interleukin-2; D015850:Interleukin-6; D011498:Protein Precursors; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone