Interleukin‐3 and Interleukin‐6 Stimulate Bovine Adrenal Cortisol Secretion Through Different Pathways

Abstract

Several interleukins have been reported to play a major role in the regulation of steroid secretion at all three levels of the hypothalamic-pituitary-adrenal axis. The objective of this study was to investigate the effect of interleukin-3 (IL-3) and interleukin-6 (IL-6) on cortisol secretion of bovine adrenocortical cells in primary culture under serum-free conditions. Both IL-3 and IL-6 stimulated basal cortisol secretion dose-dependently to a similar extent at a similar time course. After incubation with IL-3 or IL-6 at concentrations of 100 microg/l, a maximum 4.1-fold increase of the cortisol secretion was reached after 12 h (P<0.01). Coincubation of IL-3 and IL-6 (100 microg/l) revealed no significant synergism. To elucidate a possible involvement of arachidonic acid metabolites in the signal transduction, we coincubated IL-3 or IL-6 together with the cyclo-oxygenase inhibitor indometacin or the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). Coincubation with indometacin completely abolished the stimulatory effect of IL-6 but had no effect on IL-3 stimulated cortisol secretion. In contrast, specific inhibition of the lipoxygenase system by nordihydroguaiaretic acid blocked IL-3 stimulated steroidogenesis while the effect of IL-6 was not affected. Neither IL-3 nor IL-6 altered cAMP levels significantly, whereas ACTH significantly induced cAMP levels in parallel to its steroidogenic effect. In conclusion, our data indicate that IL-3 and IL-6 stimulate the steroid secretion of bovine adrenocortical cells to a similar extent and with a similar time course. However, the effects of IL-3 and IL-6 are mediated through different, cAMP-independent pathways. While the stimulatory effect of IL-3 seems to be dependent on the lipoxygenase pathway, the effect of IL-6 on adrenocortical cortisol secretion is mediated through the cyclo-oxygenase pathway.

Interleukin-6 inhibits adrenal androgen release from bovine adrenal zona reticularis cells by inhibiting the expression of steroidogenic proteins

“…In contrast, IL-6 stimulates cortisol release [17,18,[22][23][24] and the expression of steroidogenic enzymes (unpublished observation) in the ZF and adrenal androgens release from the mixed adrenocortical preparation. The mechanisms through which IL-6 stimulates steroidogenesis in a mixed adrenocortical cell population and isolated ZF cells, but inhibits steroidogenesis from ZR cells, Leydig cells, and granulosa cells are unknown, but may be related to cell-tocell interactions mediated by either cell surface molecules or molecules secreted by the adrenocortical cells.…”

“…However, recombinant murine IL-6 and recombinant bovine IL-6 from commercial sources have similar effects as the IL-6 from Dr Van Snick. Furthermore, both murine IL-6 and human IL-6 increase the release of glucocorticoids from rat, human, and bovine adrenal cells demonstrating the interaction of the human and murine IL-6 with the IL-6 receptors of different species [17,18,[22][23][24][25]. The bovine and murine IL-6 and IL-6 receptors have moderate homology.…”

“…The function of the hypothalamic-pituitary-adrenal axis is modified by IL-6 in that this cytokine stimulates CRH release from the hypothalamus, ACTH release from the pituitary, and glucocorticoid release from cells cultured from all zones of the adrenal cortex [15][16][17][18][22][23][24][25]33] and cortisol release from cells isolated from the bovine ZF [22]. However, the effects of IL-6 on adrenal androgen release have only been investigated by 2 laboratories.…”

“…In addition, glucocorticoid release from primary cultures of human, rat, and bovine adrenocortical cells is increased by incubating the cells with IL-6 [15][16][17][18][22][23][24][25]. In these cultured cells, IL-6 is probably stimulating the adrenal zona fasciculata (ZF) cells that primarily secrete glucocorticoids [1].…”

Insulin sensitization with a peroxisome proliferator-activated receptor γ agonist prevents adrenocortical lipid infiltration and secretory changes induced by a high-sucrose diet

“…In addition, the regulation of steroidogenesis by adipocyte secretory products generated by fat cells detected in close contact with steroidogenic cells has also been shown (Ehrhart-Bornstein et al 2003). The effect of circulating adipokines/cytokines (Michl et al 2000, Bornstein et al 2004, Mikhaylova et al 2007) and even of cytokines originated within the adrenal tissue must also be taken into account (Engstrom et al 2008). In particular, preliminary results from our laboratory indicate a macrophage infiltration of the adrenal cortex and increased expression levels of tumor necrosis factor a (TNFa) and interleukin 1b during the first weeks of treatment (data not shown).…”