Expression of activin/inhibin signaling components in the human adrenal gland and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis

Abstract

Activins and inhibins are structurally related glycoprotein hormones modulating pituitary FSH secretion and gonadal steroidogenesis. Activins and inhibins are also produced in the adrenal cortex where their physiological role is poorly known. Hormonally active human adrenocortical tumors express and secrete inhibins, while in mice adrenal inhibins may function as tumor suppressors. To clarify the significance of adrenal activins and inhibins we investigated the localization of activin/inhibin signaling components in the adrenal gland, and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis.Activin receptor type II/IIB and IB, activin signal transduction proteins Smad2/3, and inhibin receptor betaglycan were expressed throughout the adrenal cortex, whereas Smad4 expression was seen mainly in the zona reticularis and the innermost zona fasciculata as evaluated by immunohistochemistry. Treatment of cultured adrenocortical carcinoma NCI-H295R cells with activin A inhibited steroidogenic acute regulatory protein and 17 -hydroxylase/17,20-lyase mRNA accumulation as evaluated by the Northern blot technique, and decreased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate secretion as determined by specific enzyme immunoassays. Activin A increased apoptosis as measured by a terminal deoxynucleotidyl transferase in situ apoptosis detection method. Inhibins had no effect on steroidogenesis or apoptosis.In summary, activin/inhibin signaling components are coexpressed in the zona reticularis and the innermost zona fasciculata indicating full signaling potential for adrenal activins and inhibins in these layers. Activin inhibits steroidogenic enzyme gene expression and steroid secretion, and increases apoptosis in human adrenocortical cells. Thus, the activin-inhibin system may have a significant role in the regulation of glucocorticoid and androgen production and apoptotic cell death in the human adrenal cortex.

Inhibition of DNA methylation increases follistatin expression and secretion in the human adrenocortical cell line NCI-H295R

“…Thus, hypomethylation of the FS gene promoter could lead to relative abundance of FS, which can inhibit the effects of activin (and other TGF-family peptides) on steroidogenesis and apoptosis in adrenocortical cells (Spencer et al 1999, Vänttinen et al 2003. If, on the other hand, FS gene promoter is hypermethylated, FS gene transcription and translation will be suppressed leaving more activin available.…”

“…Interestingly, activin A suppressed cortisol and androgen production as well as the expression of steroidogenic enzyme genes in human adrenocortical cells (Vänttinen et al 2003), while in two other recent studies activin increased aldosterone production and the expression of several genes involved in steroidogenesis (Wang et al 2003, Suzuki et al 2004). Furthermore, FS was shown to prevent the activin -induced apoptotic cell death in primary cultures of human fetal adrenal cells and in the human adrenocortical cell line NCI-H295R (Spencer et al 1999, Vänttinen et al 2003.…”

Activin A stimulates catecholamine secretion from rat adrenal chromaffin cells: a new physiological mechanism

“…All data from these figures are from 5-7 cells. Vanttinen et al 2003). The secretion of activin A from the adrenal cortex suggests that paracrine signalling within the adrenal gland may be adequate to cause activin-induced catecholamine release.…”

“…Neuronal survival of rat hippocampal cultures is also promoted by activin A and this effect is blocked by Ca 2+ channel antagonists (Iwahori et al 1997). Activin signalling components are expressed in the adrenal cortex and activin A reduces secretion of several steroid hormones from this tissue (Vanttinen et al 2003). mRNA for activin A and its receptor has been identified in human fetal and adult adrenal cortical cells and cultured adrenocortical cell lines, and adrenocorticotrophin induces secretion of activin A from these cell types (Vanttinen et al 2002).…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…The physiological roles of activins and inhibins in the adrenal cortex are not completely understood. Activin A is able to reduce adrenocortical cell growth by favoring cell apoptosis (213) and to regulate expression of several steroidogenic enzymes leading to inhibition of corticosteroid secretion (213,214). Conversely, no direct action of inhibins alone on the adrenal cortex has been clearly demonstrated.…”