Prostaglandin-Dependent in Vitro Stimulation of Adrenocortical Steroidogenesis by Interleukins*

Abstract

The effects of interleukins on adrenal steroidogenesis and their mode of action were studied using cultured rat adrenal cells. The addition of rat interleukin-1 alpha (IL-1 alpha) or rat IL-2 increased corticosterone levels in the medium in a concentration-dependent manner during 24 h of incubation. The minimum, half-maximum, and maximum effective concentrations of both rat IL-1 alpha and rat IL-2 were almost same (approximately 3, 10, and 100 U/ml, respectively). After a latent period, the effect became apparent after 12 h of incubation. Human IL-1 beta and human IL-6 also showed a stimulatory effect on corticosterone production, whereas human IL-2 was inactive in this system. To clarify the cellular mechanism of these stimulatory effects, we measured the levels of prostaglandin E2 (PGE2) and cAMP in the cells and media as well as the corticosterone levels. Corticosterone production stimulated by IL-1 alpha or IL-2 was accompanied by intracellular and extracellular cAMP and PGE2 accumulation. Although the stimulation of both cAMP and corticosterone was observed only after 12 h of incubation, PGE2 levels increased during the first 4 h of incubation. Corticosterone, cAMP, and PGE2 production stimulated by ILs was almost completely blocked by the addition of 0.1 mM aspirin, a cyclooxygenase inhibitor. Lipoxygenase inhibitors, i.e. AA-861, nordihydroguaiaretic acid, and 5,8,11,14-eicosatetrynoic acid, did not abolish corticosterone production stimulated by ILs. Submaximal doses of IL-1 alpha and IL-2 synergistically stimulated PGE2 production, but did not have even additional effects on cAMP and corticosterone levels. On the other hand, submaximal doses of ACTH, which did not significantly affect PGE2 levels, acted synergistically with IL to increase cAMP and corticosterone levels in these cells. These results indicate that 1) IL-1 alpha and IL-2 directly stimulate glucocorticoid synthesis in a dose- and time-dependent manner; 2) a half-maximum effective concentration of ACTH acts synergistically with IL in stimulating glucocorticoidogenesis; 3) the stimulatory process initially requires PGs, followed by the activation of the adenylate cyclase system; 4) although the profiles of steroidogenic action of IL-1 alpha and IL-2 are quite similar, they may exert their effects through different mechanisms in their early steps of PGE2 production; and 5) the low effective concentrations of both cytokines suggest possible physiological or pathophysiological roles of circulating cytokines in the glucocorticoidogenesis under certain conditions.

Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy

“…One pathogenic mechanism might relate to perturbations in the homeostatic interplay between the HPA axis and the immune system, in the form of cytokines (Jenkins and Grossman, 1997). It has been clearly established that interleukins (ILs) 1α, IL-1β, IL-6 and IL-2 are all able to exert a direct stimulatory effect on adrenocortical cortisol secretion (Roh et al, 1987;Whitcomb et al, 1988;Salas et al, 1990;Tominaga et al, 1991;O'Connell et al, 1994), with the stimulatory effects of IL-1α and IL-1β being suggested to be mediated via prostaglandins (PGD 2 , PGF 2 and PGE 2 ) (Winter et al, 1990;Tominaga et al, 1991). Furthermore, IL-6 has been shown to act synergistically with physiological concentrations of ACTH in stimulating cortisol secretion (Salas et al, 1990).…”

Adrenocorticotropin (ACTH)- and Non-ACTH-Mediated Regulation of the Adrenal Cortex: Neural and Immune Inputs

“…IL-1 induced corticosteroid biosynthesis in vivo independently from ACTH and caused glucocorticoid secretion in hypophysectomized rats (55), perfused rat adrenals (56), and dispersed human adrenal cells (57). IL-6 stimulated corticosterone release from rat adrenocortical cells alone and in synergy with ACTH, an effect probably mediated and amplified by PGs (58). Recombinant human IL-6 also increased the secretion of cortisol and adrenal androgens in humans both via ACTH and directly.…”

Immunocytochemical Evidence for Interleukin-2 Receptor Regulation on Rat Anterior Pituitary and Adrenal Cells.

“…It is of value to be indicated that IL-2 used in this study was at the half-maximum effective concentration which induced corticosterone biosynthesis in our previous adrenal cell culture study [12]. In this study, we compared the time courses of IL-2 stimulated prostaglandin E2, cyclic AMP and corticosterone synthesis in dispersed rat adrenal cells and found that prostaglandin E2 synthesis began to increase within an hour but the stimulation of cyclic AMP and corticosterone synthesis needed more than 12 hr to be induced [27]. Why steroidogenesis requires a relatively long latent period after the initial cellular change, i.e., prostaglandin E2 synthesis is one of the major unanswered questions in this study.…”

“…Primary cultures of enzymatically dispersed rat anterior pituitary cells and adrenal cells were prepared as described previously [27], except that the cells were plated on glass coverslips at a density of 2 x 105 cells. All experiments were done 3 days after plating.…”

“…Among these findings, we considered that the P-A activation is particularly important, since glucocorticoids have a variety of immuno-suppressive and anti-inflammatory actions, including decreases in IL-2 production [11] and IL-2R expression [10,23] in the lymphocytes. So far, IL-2 was reported to activate the P-A function at the level of the hypothalamus [6], pituitary [5,19,25], and the adrenals [27] . However, in spite of the extensive characterization of IL-2 signaling in the immune tissues [10,18,20,23,24], information concerning the cellular or subcellular mechanisms of IL-2 action in the endocrine system is quite limited [2,25] .…”