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N. Hanley, B. C. Williams, M. Nicol, I. M. Bird, and S. W. Walker


Using tritiated-thymidine incorporation as a measure of cell growth, interleukin-1β stimulated the growth of bovine zona fasciculata/reticularis adrenocortical cells after 72h in primary culture. Within the range of 10–1000pg/ml, interleukin-1β produced over 40% of angiotensin II-stimulated [3H]thymidine incorporation (P<0.005 compared with basal for 10pg/ml and 1000pg/ml; P<0.05 for 100pg/ml; two-tailed unpaired Student's t-test). Interleukin-1β did not directly stimulate cortisol secretion.

By stimulating adrenocortical growth, the increase in interleukin-1 during fever provides a potential mechanism for chronically raising glucocorticoid output. This study is the first demonstration of a long-term effect involving interleukin-1β on the adrenal cortex.

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S. Kapas, C. D. Orford, S. Barker, G. P. Vinson, and J. P. Hinson


The intracellular mechanisms of action of α-MSH in rat adrenocortical cells were examined. When rat adrenal capsule (largely glomerulosa) cells were stimulated with a range of concentrations of α-MSH there was significant stimulation of aldosterone secretion at 10-10 mol/l, although cyclic AMP was not increased until high concentrations of α-MSH were used (10-6 mol/l and above). However, cells incubated with ACTH showed an increase in aldosterone secretion at 10-11 mol/l and levels of cyclic AMP were elevated at 10-9 mol ACTH/1.

When rat adrenal whole capsules were incubated with α-MSH, membrane-bound protein kinase C (PKC) activity was increased and cytosolic enzyme activity decreased, showing PKC activation. Stimulation with angiotensin II also induced translocation of PKC activity, but ACTH did not.

When [3H]inositol-loaded glomerulosa cells were stimulated with α-MSH there was significant generation of [3H]inositol trisphosphate (IP3) at concentrations of α-MSH which stimulated secretion of aldosterone. Significantly increased levels of [3H]IP3 were also measured when loaded cells were exposed to angiotensin II. ACTH did not cause any significant stimulation of [3H]IP3 production at any concentration used. These results indicate that activation of PKC and phospholipase C is important in modulating the steroidogenic effect of α-MSH.

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C Delarue, JM Conlon, I Remy-Jouet, A Fournier, and H Vaudry

Besides the classical corticotropic hormones, ACTH and angiotensin II, various regulatory peptides produced by the adrenal gland are thought to participate in the control of corticosteroid secretion. Here, we review the evidence that endothelins (ETs) synthesized within the adrenal cortex may act as autocrine and/or paracrine factors to regulate adrenocortical cell activity. The expression of ETs has been detected in normal, hyperplastic and neoplastic adrenocortical cells. The occurrence of ET receptors has been described in the different zones of the cortex. ETs stimulate the secretion of both glucocorticoids and mineralocorticoids, and modulate the proliferation of adrenocortical cells. The effects of ETs on steroidogenic cells are mediated through the activation of various signaling mechanisms including stimulation of phospholipase C, phospholipase A2 and adenylyl cyclase activity, as well as calcium influx through plasma channels. These observations suggest that locally produced ETs may play an important role in the regulation of corticosteroid secretion and in the control of mitogenesis in normal and tumoral adrenocortical cells.

Free access

Namita G Hattangady, Shigehiro Karashima, Lucy Yuan, Daniela Ponce-Balbuena, José Jalife, Celso E Gomez-Sanchez, Richard J Auchus, William E Rainey, and Tobias Else

Somatic and germline mutations in the inward-rectifying K+ channel (KCNJ5) are a common cause of primary aldosteronism (PA) in aldosterone-producing adenoma and familial hyperaldosteronism type III, respectively. Dysregulation of adrenal cell calcium signaling represents one mechanism for mutated KCNJ5 stimulation of aldosterone synthase (CYP11B2) expression and aldosterone production. However, the mechanisms stimulating acute and chronic production of aldosterone by mutant KCNJ5 have not been fully characterized. Herein, we defined the effects of the T158A KCNJ5 mutation (KCNJ5T158A) on acute and chronic regulation of aldosterone production using an adrenal cell line with a doxycycline-inducible KCNJ5T158A gene (HAC15-TRE-KCNJ5T158A). Doxycycline incubation caused a time-dependent increase in KCNJ5T158A and CYP11B2 mRNA and protein levels. Electrophysiological analyses confirm the loss of inward rectification and increased Na+ permeability in KCNJ5T158A-expressing cells. KCNJ5T158A expression also led to the activation of CYP11B2 transcriptional regulators, NURR1 and ATF2. Acutely, KCNJ5T158A stimulated the expression of total and phosphorylated steroidogenic acute regulatory protein (StAR). KCNJ5T158A expression increased the synthesis of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol, measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). All of these stimulatory effects of KCNJ5T158A were inhibited by the L-type Ca2+ channel blocker, verapamil. Overall, KCNJ5T158Aincreases CYP11B2 expression and production of aldosterone, corticosterone and hybrid steroids by upregulating both acute and chronic regulatory events in aldosterone production, and verapamil blocks KCNJ5T158A-mediated pathways leading to aldosterone production.

Free access

RH Foster

The main regulators of aldosterone secretion in adrenal gland zona glomerulosa (ZG) cells are the hormones angiotensin II (Ang II) and adrenocorticotrophin (ACTH) and small increases in the extracellular potassium (K(+)) concentration. The action of these agonists is mediated by different signalling systems - ACTH is mediated by cAMP and activation of protein kinase A while Ang II and K(+) activate two protein kinases, Ca(2+)-calmodulin-dependent protein kinase (CamK) and diacylglycerol-dependent protein kinase (PKC). Ang II, besides being one of the main agonists for the secretion of aldosterone, also stimulates proliferation of ZG cells, a process mediated by mitogen-activated protein kinases (MAPKs). Recent studies aimed at elucidating the molecular mechanisms underlying cell proliferation have shown that calcineurin is the principal regulator of MAPKs activity. The purpose of this review is to discuss experimental evidence of possible reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in ZG cells.

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Andreas Hoeflich and Maximilian Bielohuby

The adrenal gland influences a multitude of processes during stress response, but also potently affects the immune system, glucose metabolism, electrolyte or water homeostasis, and cardiovascular functions. According to the present understanding, the adrenal cortex is tightly controlled by the hypothalamic–pituitary–adrenal axis. This axis involves hypothalamic CRH and pituitary ACTH which determine processes of adrenocortical growth and function. However, control of the adrenal gland comprises a plethora of additional endogenous or exogenous factors. Among those are diverse hormones, psychosocial parameters, physiological stress, secondary plant products, or even environmental pollutants. In the present review, we summarize the current view of endocrine growth control in the adrenal gland. We then discuss intracellular mechanisms of adrenal growth control and focus on extracellular signal regulated kinases 1/2 (ERK1/2), which have been demonstrated to be controlled by not only ACTH or angiotensin II, but also by a large number of additional effectors. On the basis of these multiple exogenous or endogenous factors which impact on the adrenal gland through ERK1/2 activity, we speculate on a mechanism by which ERK1/2 act as a central integrative growth regulatory elements in the adrenal gland.

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S Kapas, A Purbrick, S Barker, G P Vinson, and J P Hinson


It is well established that ACTH and angiotensin II (Ang II) stimulate aldosterone secretion from rat adrenal zona glomerulosa cells in vitro and mediate their steroidogenic effects via the cyclic AMP (cAMP) pathway and phosphoinositide turnover respectively. α-MSH also stimulates aldosterone secretion from zona glomerulosa cells in vitro, and recent studies from our laboratory have shown that its steroidogenic effects are mediated by increases in inositol 1,4,5-trisphosphate (IP3) production. α-MSH also stimulates adenylyl cyclase activity, but only at concentrations that are supramaximal for stimulation of steroidogenesis. The observation that α-MSH-stimulated IP3 accumulation declines as the activity of adenylyl cyclase increases prompted further studies on the interactions of cAMP and phosphoinositide production.

The effects of α-MSH and ACTH on Ang II-stimulated steroidogenesis and IP3 accumulation were studied. On addition of increasing concentrations of ACTH, both the aldosterone and IP3 responses to Ang II were significantly inhibited; however, only high concentrations of α-MSH achieved this effect. These results suggest that cAMP or a cAMP-dependent event is able to inhibit phospholipase C activity. This hypothesis was tested by measuring IP3 production in Ang II-stimulated zona glomerulosa cells exposed to two different concentrations of α-MSH: 1 nmol/l, which stimulates the generation of IP3, and 1 μmol/l, which activates adenylyl cyclase. It was found that this high concentration of α-MSH significantly inhibited Ang II-stimulated aldosterone secretion and IP3 levels. In addition, α-MSH reduced 125I-labelled Ang II binding to rat adrenal zona glomerulosa cells. ACTH and cAMP also inhibited Ang II binding, thus supporting the hypothesis that cAMP (or a cAMP-mediated event) inhibits Ang II receptor function.

Open access

Rebecca J Gorrigan, Leonardo Guasti, Peter King, Adrian J Clark, and Li F Chan

The melanocortin-2-receptor (MC2R)/MC2R accessory protein (MRAP) complex is critical to the production of glucocorticoids from the adrenal cortex. Inactivating mutations in either MC2R or MRAP result in the clinical condition familial glucocorticoid deficiency. The localisation of MC2R together with MRAP within the adrenal gland has not previously been reported. Furthermore, MRAP2, a paralogue of MRAP, has been shown in vitro to have a similar function to MRAP, facilitating MC2R trafficking and responsiveness to ACTH. Despite similar MC2R accessory functions, in vivo, patients with inactivating mutations of MRAP fail to be rescued by a functioning MRAP2 gene, suggesting differences in adrenal expression, localisation and/or function between the two MRAPs. In this study on the rat adrenal gland, we demonstrate that while MRAP and MC2R are highly expressed in the zona fasciculata, MRAP2 is expressed throughout the adrenal cortex in low quantities. In the developing adrenal gland, both MRAP and MRAP2 are equally well expressed. The MC2R/MRAP2 complex requires much higher concentrations of ACTH to activate compared with the MC2R/MRAP complex. Interestingly, expression of MC2R and MRAP in the undifferentiated zone would support the notion that ACTH may play an important role in adrenal cell differentiation and maintenance.

Free access

M Hołysz, N Derebecka-Hołysz, and W H Trzeciak

The study was designed to elucidate the influence of the protein kinase A (PKA) signal transduction pathway on transcription of the LIPE gene encoding hormone-sensitive lipase/cholesteryl esterase (HSL) in H295R cells. HSL is one of the key enzymes involved in steroid hormone synthesis, and ACTH, with mediation of the PKA pathway, increases its activity. However, the mode of regulation of LIPE gene expression by ACTH remains unknown. It was found that stimulation of the PKA pathway by the adenylyl cyclase activator, forskolin, caused a twofold increase in LIPE transcript accompanied by appreciable rise in the protein product of the gene and cortisol output. RNA polymerase II inhibitor abolished, and protein synthesis inhibitor attenuated this effect. Forskolin and PKA catalytic subunit increased transcriptional activity of LIPE promoter A in cells transfected with the luciferase reporter vector. Overexpression of steroidogenic factor-1 (SF-1) increased LIPE promoter activity, while transient silencing of SF-1 expression with specific siRNAs abolished forskolin-stimulated LIPE transcription. It is concluded that ACTH via the PKA pathway stimulates expression of SF-1, which activates transcription of LIPE presumably by interaction with putative binding sequences within promoter A. A novel mechanism contributing to the long-term effect of ACTH on adrenal steroidogenesis is proposed: ACTH stimulates transcription of SF-1, which interacts with the putative SF-1-binding sequences within the promoter and activates LIPE transcription. An increased level of HSL results in an enhanced supply of cholesterol required for steroid hormone synthesis.

Free access

Amanda J Rickard and Morag J Young

The mineralocorticoid receptor (MR) and glucocorticoid receptor are ligand-activated transcription factors that have important physiological and pathophysiological actions in a broad range of cell types including monocytes and macrophages. While the glucocorticoids cortisol and corticosterone have well-described anti-inflammatory actions on both recruited and tissue resident macrophages, a role for the mineralocorticoid aldosterone in these cells is largely undefined. Emerging evidence, however, suggests that MR signalling may promote pro-inflammatory effects. This review will discuss the current understanding of the role of corticosteroid receptors in macrophages and their effect on diseases involving inflammation, with a particular focus on cardiovascular disease.