Stimulation by Interleukin-6 and Inhibition by Tumor Necrosis Factor of Cortisol Release from Bovine Adrenal Zona Fasciculata Cells Through Their Receptors

Abstract

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are synthesized and released from adrenal cells. Therefore, the effects of TNF-alpha and IL-6 on cortisol release from bovine zona fasciculata (ZF) cells were investigated. IL-6 (10-1000 pg/mL) significantly increased basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol release in a concentration-dependent manner. This stimulatory effect of IL-6 became apparent at intervals as short as 4 h and continued through 24 h. IL-6 also potentiated the cortisol release stimulated by the adenylyl cyclase activator forskolin. By contrast, TNF-alpha (0.1-10 ng) inhibited basal and ACTH-stimulated cortisol release in a concentration-dependent manner. The inhibitory effects of TNF-alpha on cortisol release were significant at time intervals as short as 4 h and continued through 24 h. TNF-alpha inhibited forskolin-stimulated cortisol release. Binding studies demonstrated that ZF cells have IL-6 receptors (100 receptors/cell, Kd of 7.5 x 10(-11)) and TNF receptors (200 receptors/cell, Kd of 2.4 x 10(-9) M). Immunohistochemical analysis provided evidence that the majority of ZF cells have IL-6 receptors, TNF type 1 receptors, and TNF type 2 receptors. Because IL-6 and TNF-alpha are released from the adrenal cortex and these cytokines modify the release of cortisol from the ZF, IL-6 and TNF-alpha may play a paracrine or autocrine role in the regulation of adrenal function.

Cortisol response to ACTH stimulation correlates with blood interleukin 6 concentration in healthy humans

“…IL6 receptors are present in the adrenal cortex of many species, including humans (3,(19)(20)(21). It has been shown that IL6 alone stimulates glucocorticoid release from primary cultures of rat, bovine and human adrenal cells (19)(20)(21)(22)(23).…”

“…It has been shown that IL6 alone stimulates glucocorticoid release from primary cultures of rat, bovine and human adrenal cells (19)(20)(21)(22)(23). However, in order to stimulate glucocorticoid release, a long incubation time (O12 h) is required.…”

“…However, in order to stimulate glucocorticoid release, a long incubation time (O12 h) is required. IL6 also acts in synergy with ACTH, and in the presence of ACTH IL6 increases glucocorticoid release even at times when, alone, it is ineffective (19,22). In mice ACTH is a necessary permissive factor that enables IL6 to stimulate glucocorticoid secretion, at least during the first 36 h of viral infection (7).…”

Improvement of ACTH response to insulin tolerance test in female patients with rheumatoid arthritis due to tumor necrosis factor inhibition

“…This finding could indicate a better ACTH release with adrenal gland stimulation but not one sufficient to reach normal cortisol serum levels. Barney and colleagues found in bovine adrenal cells that TNF has an inhibitory effect on ACTH-stimulated cortisol released (23), therefore, we could be improving this balance in the adrenal cells. However, the anti-TNF-a therapy not only demonstrates TNF neutralization but also diminishes the interleukin(IL)-6 and IL-1 levels to some degree.…”

The endotoxin-induced increase of cytokines is followed by an increase of cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects

“…Some key mediators of increased serum levels of cortisol relative to DHEA, DHEAS or 17OH-progesterone may be (a) circulating cytokines such as TNF and IL-6, which exert their specific effects at the level of the adrenocortical cell (Jäättelä et al 1991, Päth et al 1996, Barney et al 2000, (b) local immune cells in the adrenal gland, which produce cytokines or act via surface molecules (Wolkersdorfer et al 1999), and (c) neurotransmitters or neuropeptides of innervating nerves of the adrenal glands, whose release may be under control of local cytokines (Ehrhart-Bornstein et al 1998). Since TNF can inhibit the secretion of cortisol from adrenal cells due to an inhibition of the P450c21 or other factors (Jäättelä et al 1991, Barney et al 2000, and IL-6 increases cortisol secretion (Päth et al 1996, Barney et al 2000, these cytokines may be relevant for early increased secretion of cortisol relative to DHEA, DHEAS or 17OH-progesterone during endotoxinaemia or chronic inflammatory diseases.…”