DIFFERENTIAL DEPENDENCE OF ACTH-SECRETION INDUCED BY VARIOUS CYTOKINES ON THE INTEGRITY OF THE PARAVENTRICULAR NUCLEUS

Effect of different cytokines, human recombinant interleukin-1 alpha a nd beta (IL-1 alpha, IL-1 beta), interleukin-6 and tumor necrosis fact or-alpha (TNF) on adrenocorticotropin (ACTH) secretion was compared in sham-operated rats and those with lesions of the hypothalamic paraven tricular nucleus. IL-1 alpha was less active than IL-1 beta in stimula ting ACTH in sham-operated rats. Intravenous injection of IL-1 beta 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 f actor-41, the response to IL-1 beta was attenuated but not abolished. This suggests involvement of extra-paraventricular releasing factors i n mediation of ACTH-releasing activity of IL-1 beta, altered responsiv eness of pituitary to CRFs, and/or direct action of IL-IP on the corti cotrope cells, TNF resulted in a biphasic stimulation of ACTH concentr ation, with peaks at 15 min and 90 min, in paraventricular-lesioned, T NF 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 intrave nously injected cytokines, the peak was at 1 h in sham-lesioned rats. Paraventricular lesion completely prevented the increase of ACTH plasm a 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-1 beta is able to release ACTH even in the absence of hypothalamic drive,