Interleukin-1β Enhances Corticosterone Secretion by Acting Directly on the Rat Adrenal Gland

Abstract

Interleukin-1 (IL-1), a monokine released by activated monocytes during the acute phase of the inflammatory responses, has been reported to enhance hypophyseal ACTH release mainly by stimulating hypothalamic CRF secretion. We investigated a possible direct effect of IL-1 beta on the adrenal gland of the rat. IL-1 beta was found to dose-dependently (4-8 micrograms/kg) raise corticosterone (B) blood concentration in hypophysectomized rats, without inducing any significant increase in the level of circulating ACTH. IL-1 beta did not affect B production by either isolated rat inner adrenocortical cells or fragments of adrenocortical autotransplants lacking chromaffin cells, but dose-dependently (10(-8)-10(-6) M) enhanced that by adrenal slices including both cortex and medulla. The secretory effect of IL-1 beta (10(-6) M) was completely blocked by both alpha-helical-CRF (10(-6) M) and corticotropin-inhibiting peptide (10(-6) M), two competitive inhibitors which (at these concentrations) were able to annul B response of adrenal slices to CRF (10(-6) M) and ACTH (10(-8) M), respectively. In light of many findings indicating that adrenal medulla contains and releases CRF and numerous POMC-derived peptides (including ACTH), the hypothesis is advanced that the mechanism underlying the direct secretory effect of IL-1 beta on the adrenal gland may involve the activation of an intraadrenal CRF/ACTH system.

Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function

“…These findings support the hypothesis of the existence of an intraadrenal CRH system. 5,17 Within the adrenal itself, CRH-like immunoreactivity has been detected in the medulla of humans and other species. 18,19 This adrenal CRH is identical to the hypothalamic CRH and is released in response to physiological stimuli such as hemorrhage, 20 splanchnic nerve activation, 21,22 K + -induced depolarization, nicotine, 23 and various neuropeptides and cytokines.…”

“…In addition, the presence of CRH-R1 receptors on immune cells and the documented steroidogenic action of immune mediators such as interleukin-1 5,36 and interleukin-6, 37,38 also suggest an intraadrenal paracrine CRH/immune peptide axis which may contribute to the increase in cortisol production by adrenocortical cells as well. Participation of the CRH-R1 in intraadrenal cortisol regulation, in the process of inflammation, 39,40 and in the syndrome of ectopic CRH production seem to justify clinical trials in pathologic states with the above mentioned conditions.…”

“…4 CRH also activates both the adrenomedullary and systemic sympathetic system limbs and an intraadrenal CRH/ACTH/cortisol system has been postulated. 5 Recently, the CRH-R1 has been demonstrated in mid-gestation human fetal adrenals and CRH has been shown to stimulate directly adrenal steroidogenesis in human fetal adrenal cells via the phospholipase C-inositol phosphate second messenger system. 6,7 Since several mental disorders, including melancholic depression, 8 anxiety disorders, 9,10 and Alzheimer's disease, 8 are associated with hyperactivation of the HPA axis and the sympathetic system, it is of major interest to identify substances which selectively inhibit the activity of these systems.…”

Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors

“…The 41-aminoacid hypothalamic peptide corticotropin releasing hormone (CRH) (Sawchenko & Swanson, 1985), a major activator of the hypothalamic-pituitary-adrenal (HPA) response to stress (Gold et al, 1986), has been detected in various tissues, including the adrenal (Andreis et al, 1991), the spleen (Webster & Desousa, 1983), the testis (Dufau et al, 1993), and the placenta (Petraglia et al, 1987). Interestingly, CRH has also been found in in¯ammatory cells from human blood (Stephanou et al, 1990).…”

Effect of Interleukin-1β on Plasma ACTH, β-Endorphin, and Corticosterone Levels in Infant and Prepubertal Rats

“…Interactions between the immune system and the HPAA are of particular interest, because they are both associated in the adaptive response to stress. The main target of the IL-1P effect on the HPAA is believed to be the stimulation of Received July 12, 1994; accepted December 19, 1994 C R H secretion (11-13), but it has been shown to exert a direct effect on the pituitary and on adrenal hormone secretion as well (14,15). It is to be elucidated if activation of the HPAA by IL-1P is a specific effect or if it represents a nonspecific stress reaction.…”