AbstractEffect of different cytokines, human recombinant interleukin‐la and fl (IL‐1 a, 1L‐1 j), interleukin‐6 and tumor necrosis factor‐a (TNF) on adrenocorticotropin (ACTH) secretion was compared in sham‐operated rats and those with lesions of the hypothalamic paraventricular nucleus. IL‐1 a was less active than IL‐1 b in stimulating ACTH in sham‐operated rats. Intravenous injection of IL‐1 fl in sham‐operated animals resulted in a rapid elevation of ACTH secretion. Five days after surgical lesion of the paraventricular nucleus, the main hypothalamic source of hypophysiotropic corticotropin‐releasing factor‐41, the response to IL‐1 /I was attenuated but not abolished. This suggests involvement of extra‐paraventricular releasing factors in mediation of ACTH‐releasing activity of IL‐1 P, altered responsiveness of pituitary to CRFs, and/or direct action of IL‐1 j on the corticotrope cells. TNF resulted in a biphasic stimulation of ACTH concentration, with peaks at 15 min and 90 min. In paraventricular‐lesioned, TNF injected rats both of these ACTH peaks disappeared, suggesting that CRFs from the paraventricular origin mediates ACTH‐inducing activity of TNF. IL‐6 elevated ACTH secretion much later than the other intravenously injected cytokines, the peak was at 1 h in sham‐lesioned rats. Paraventricular lesion completely prevented the increase of ACTH plasma levels after IL‐6 injection. These data suggest that: (1) Effect of TNF and IL‐6 on hypothalamo‐pituitary‐adrenal axis is mediated through the hypothalamic paraventricular nucleus and (2) IL‐lB is able to r