Differential Dependence of ACTH Secretion Induced by Various Cytokines on the Integrity of the Paraventricular Nucleus

Abstract

Effect of different cytokines, human recombinant interleukin-1 alpha and beta (IL-1 alpha, IL-1 beta), interleukin-6 and tumor necrosis factor-alpha (TNF) on adrenocorticotropin (ACTH) secretion was compared in sham-operated rats and those with lesions of the hypothalamic paraventricular nucleus. IL-1 alpha was less active than IL-1 beta in stimulating 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 factor-41, the response to IL-1 beta was attenuated but not abolished. This suggests involvement of extra-paraventricular releasing factors in mediation of ACTH-releasing activity of IL-1 beta, altered responsiveness of pituitary to CRFs, and/or direct action of IL-1 beta 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-1 beta is able to release ACTH even in the absence of hypothalamic drive.

Rat brain vascular distribution of interleukin‐1 type‐1 receptor immunoreactivity: Relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli

“…Interestingly, we consistently found IL-1R1-and COX-2-positive vessels in the hypothalamic structures known to play a role in the fever and neuroendocrine responses to peripheral immune activation (Horn et al, 1994;Kovacs and Elenkov, 1995;Caldwell et al, 1998;Lu et al, 2001). In contrast, weaker and less consistent vascular IL-1R1-ir and IL-1␤-or LPS-induced COX-2-expression was observed in basomedial hypothalamic, limbic, and thalamic structures, that is, in those structure where LPS-or IL-1␤-induced Fos expression is not affected by PG synthesis inhibitors.…”

Proinflammatory cytokines regulate FcαR expression by human mesangial cells in vitro

“…In fact, biphasic stimulation of several other genes, such as junB and ACTH, has been observed in response to IL-6 or TNF-a [43][44][45].…”

Review: Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis

“…Observations of pulsatile ACTH secretion after complete lesioning of the PVN (and elimination of CRH from the ME) have revealed a surprising degree of residual pituitary-adrenocortical activity (Boyle et al 1997). Total PVN lesioning was still accompanied by an ACTH response to some cytokines (Kovacs & Elenkov 1995), and electrical lesions that destroyed the entire hypothalamus did not prevent a response to the stress of laparotomy (Witorsch & Brodish 1972). One explanation for these results is that the lesions eliminate not only hypothalamic corticotrophin-releasing factors but also inhibitory factors which may be acting to block the secretion of ACTH from the anterior pituitary.…”