Description:
<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>DESIGN</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>PATIENTS</jats:title><jats:p>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%.</jats:p></jats:sec><jats:sec><jats:title>MEASURMENTS</jats:title><jats:p>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 radioimmunoassays. Cortisol was assayed by an enzyme‐linked immunosorbent assay.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Interleukin‐2 treatment significantly increased plasma big‐endothelin levels (<jats:italic>P</jats:italic> < 0.01 <jats:italic>vs </jats:italic>basal) and endothelin‐1 levels (<jats:italic>P</jats:italic> < 0.05 <jats:italic>vs </jats:italic>basal) within two hours and this was followed by an increase in ACTH (<jats:italic>P</jats:italic> < 0.01 <jats:italic>vs </jats:italic>basal) and cortisol (<jats:italic>P</jats:italic> < 0.05 <jats:italic>vs </jats:italic>basal) within three hours. Interleukin‐6 levels increased two hours after interleukin‐2 administration (<jats:italic>P</jats:italic> < 0.01 <jats:italic>vs </jats:italic>basal). Interleukin‐2 had no detectable effect on AVP, blood pressure or heart rate.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Our data demonstrate that cytokines are able to activate the human hypothalamo‐pituitary‐adrenal axis <jats:italic>in vivo</jats:italic>. On the basis of the observed time kinetics and in connection with previous findings from <jats:italic>in vitro</jats:italic> 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.</jats:p></jats:sec>