RECOMBINANT INTERLEUKIN-6 ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN HUMANS

The inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha and -beta (IL-1 alpha and -beta), and IL-6 can activate the hyp othalamic-pituitary-adrenal (HPA) axis. Tumor necrosis factor-alpha an d IL-I have been tested in both experimental animals and humans, but t heir administration has been limited by significant toxicity, mainly s evere hypotension. IL-6, on the other hand, has demonstrated modest to xicity in animals. We evaluated the ability of recombinant IL-6 to sti mulate the human HPA axis in patients with cancer and a good performan ce status, who received daily morning sc injections of 30 mu g/kg IL-6 for 7 consecutive days, during the course of a phase I trial. IL-6 ca used impressively marked and prolonged elevations of plasma ACTH and c ortisol on the first day and blunted ACTH responses on the seventh day of treatment, perhaps as a result of increased baseline cortisol leve ls. The overall cortisol response, however, on the seventh day was of similar magnitude, suggesting that a new equilibrium in the feedback r egulation of the HPA axis occurs with chronic IL-6 administration. The toxic effects of IL-6 were modest, suggesting that it might be useful for clinical testing of the HPA axis, as an alternative to the insuli n tolerance test.