INTERFERON-ALPHA STIMULATES THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS INVIVO AND INVITRO

The successful therapeutic use of interferon-a (IFN-a) in myeloprolife rative disorders offered the possibility to test its acute and long-te rm effects on the hypothalamic-pituitary-adrenal (HPA) axis in humans. ACTH and cortisol plasma concentrations were measured in 8 patients h ourly starting from 4 p.m. through 12 p.m. on three occasions. The fir st time all patients were studied before initiation of therapy, when t he vehicle was injected alone. The patients were studied again on day 1 of IFN-alpha therapy (5 million units) and once more after 3 weeks o f therapy. On the control day, plasma concentrations of ACTH and corti sol were in the range expected for this time of day. In contrast, afte r the first administration of IFN-alpha a significant stimulation of t he HPA axis was observed. After 3 weeks of IFN-alpha therapy, no signi ficant stimulation of the HPA axis occurred after administration of IF N-alpha. IFN-alpha-induced adaptive changes in the HPA axis were also indicated by a significantly enhanced ACTH and cortisol response to ex ogenously administered supramaximal doses of corticotropin-releasing h ormone (CRH) when the patients had been on IFN-alpha treatment for 3 w eeks. To determine the exact locus of the IFN-alpha action, in vitro e xperiments were performed using rat hypothalamic organ and primary pit uitary and adrenal cell culture systems. Thereby a significant stimula tion of hypothalamic CRH secretion and rat adrenal corticosterone prod uction was observed after INF-alpha at concentrations of 5 x 10(-8) M or 10(-7) M respectively. In contrast, no direct IFN-alpha effect on p ituitary ACTH secretion could be observed in vitro. It is concluded th at IFN-alpha stimulates the HPA axis. The locus of action seems to be the hypothalamus, as well as the adrenal glands.