PubMed · 14244455
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D S DURIC, J V MICIC, J TUFEGDZIC LJALJEVIC, M STOJANOVIC. 1964. [ADRENAL CORTEX FUNCTION IN HYPERTHROIDISM].. https://pubmed.ncbi.nlm.nih.gov/14244455/
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The human adrenal cortex is a complex endocrine organ that secretes mineralocorticoids, glucocorticoids and adrenal androgens. These steroids arise from morphologically and biochemically distinct zones of the adrenal gland. Studying secretion of these distinct steroid hormones can make use of cells isolated from the adrenal gland but this requires animal sacrifice and the need for continued isolation for long-term studies. In addition primary cultures of adrenal cells have a limited life-span in culture and the cultured cells are often contaminated by the presence of non-steroidogenic cells. For that reason in vitro cell culture models have several benefits for research on adrenocortical function. Herein we discuss the available adrenocortical cell lines and their uses as model systems for adrenal studies. Focus is placed on the human NCI-H295 and mouse Y-1 adrenal cell lines, which have been used extensively as adrenocortical model systems. These cell lines have proven to be of considerable value in studying the molecular and biochemical mechanisms controlling adrenal steroidogenesis. The current review will discuss the attributes and limitations of the currently available adrenocortical cell lines as models for adrenal studies.
Atypical depression has been linked to low hypothalamic-pituitary-adrenocortical axis activity and exhibits physical and affective symptoms resembling those of glucocorticoid deficiency. Because atypical depression has also been defined by preferential responsiveness to monoamine oxidase inhibitors (MAO-I), we hypothesized that MAO-I reverse these abnormalities by interfering with glucocorticoid feedback and increasing hypothalamic-pituitary-adrenocortical activity. To test this hypothesis, we measured plasma hormones and ACTH secretagogue gene expression in male C57BL/6 mice treated chronically with saline vehicle or phenelzine, a representative MAO-I. Changes in glucocorticoid feedback were evaluated using adrenalectomized (ADX) mice with and without corticosterone replacement. Antidepressant efficacy was confirmed by decreased immobility during forced swim testing. Phenelzine significantly increased circadian nadir and postrestraint plasma corticosterone levels in sham-operated mice, an effect that correlated with increased adrenocortical sensitivity to ACTH. Phenelzine increased circadian nadir, but not poststress ACTH in ADX mice, suggesting that phenelzine augmented corticosterone secretion in sham-operated mice by increasing stimulation and decreasing feedback inhibition of hypothalamic-pituitary activity. Consistent with the latter possibility, phenelzine significantly increased plasma ACTH and paraventricular hypothalamus CRH mRNA in ADX, corticosterone-replaced mice. Phenelzine did not increase paraventricular hypothalamus CRH or vasopressin mRNA in ADX mice lacking corticosterone replacement. We conclude that chronic phenelzine treatment induces sustained increases in glucocorticoids by impairing glucocorticoid feedback, increasing adrenocortical responsiveness to ACTH, and increasing glucocorticoid-independent stimulation of hypothalamic-pituitary activity. The resulting drive for adrenocortical activity could account for the ability of MAO-I to reverse endocrine and psychiatric symptoms of glucocorticoid deficiency in atypical depression.
Activation of the hypothalamo-pituitary-adrenal axis by bacterial lipopolysaccharide (LPS; endotoxin) is well documented, although there has been uncertainty about whether LPS exerts a direct effect at the level of the adrenal. The present study found that LPS caused a dose-dependent stimulation of basal cortisol secretion by the human adrenocortical cell line, NCI-H295R, without affecting aldosterone. The expression of both Toll-like receptor 2 (TLR2) and TLR4 was demonstrated in these cells, and the specific ligands for TLR4 (purified LPS and lipid A) and TLR2 (Pam3Cys) were found to stimulate cortisol release, suggesting that these receptors may mediate the effects of LPS in adrenal cells, as has been shown in other cell types. LPS was also found to stimulate prostaglandin E2 release by these cells. The effects of LPS on cortisol were attenuated in the presence of both indomethacin and a specific COX-2 inhibitor, but not a COX-1 inhibitor, suggesting an obligatory role for COX-2 activation and prostaglandin synthesis in the adrenal response to LPS.