Aberrant interleukin-1 receptors in a cortisol-secreting adrenal adenoma causing Cushing's syndrome.
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Adenoma↗
Biomedical subjects
M Ehrhart-Bornstein
Publications and source records attributed to M Ehrhart-Bornstein.
Intraadrenal interactions in the regulation of adrenocortical steroidogenesis.
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Adrenal Cortex↗
Basal steroidogenic activity of adrenocortical cells is increased 10-fold by coculture with chromaffin cells.
Historically, catecholamine-producing chromaffin cells and steroid-producing adrenocortical cells have been regarded as two independent endocrine systems that are united under a common capsule to form the adrenal gland. There is increasing evidence for bidirectional interactions, with regulatory influences of adrenocortical secretory products on adrenomedullary functions and vice versa. However, the direct involvement of chromaffin cells on the regulation and maintenance of cortical function has not yet been demonstrated. Therefore, we analyzed glucocorticoid secretion and P450 messenger RNA (mRNA) expression in bovine adrenocortical cells in cocultures with chromaffin cells compared with those in pure cortical cell cultures. Cortisol release from cortical cells in coculture with chromaffin cells was 10 times as high (mean +/- SEM, 1035 +/- 119%) as that from the same number of isolated cortical cells (100 +/- 11%). By a [3H]thymidine incorporation assay, it was demonstrated that this effect was not due to a higher proliferation rate. Northern analysis revealed an increasing expression of P450(17alpha) mRNA in the coculture from days 1-5, whereas in isolated cortical cells, P450(17alpha) mRNA decreased, leading to a 6-fold difference on day 5. Inhibitors of protein (cycloheximide) or RNA (actinomycin D) synthesis completely annulled the observed increase in cortisol release, indicating that de novo protein synthesis is required for this activation of adrenocortical steroidogenesis. Addition of the cyclooxygenase inhibitor indomethacin reduced the stimulatory effect, suggesting that this stimulation is in part mediated by PGs. Locally produced ACTH, catecholamines, and interleukin-1 accounted for 43% of the effect. Secretory products of chromaffin cells that act in concert are believed to be responsible for the stimulation of steroidogenesis in the coculture. The coculture system is an in vitro model that corresponds to the in vivo situation in the intact adrenal gland, where both endocrine cell systems are in close contact. Our data demonstrate the requirement of intraadrenal cellular communication for the full strength of the adrenocortical hormonal response.
Adrenal Cortex↗
Morphological and functional studies of the paracrine interaction between cortex and medulla in the adrenal gland.
Within the last years it has become evident that besides the hypothalamo-pituitary-adrenal axis, extrapituitary mechanisms exist that regulate the activity of the adrenal cortex. In this context, intra-adrenal regulatory mechanisms play an important role. Several secretory products from adrenomedullary cells are able to influence adrenocortical steroidogenesis. Since the main blood flow within the adrenal is directed centripetally from the cortex to the medulla, chromatin cells should act on cortical cells in a paracrine manner. The morphological prerequisite for this regulatory pathway is seen in the close apposition of the two tissues. Within the mammalian adrenal, the two endocrine tissues are interwoven to an astonishing degree with cortical cells located within the medulla and vice versa. It is concluded from morphological and functional studies that paracrine interactions between cortex and medulla play an important role in the regulation of adrenocortical steroidogenesis.
Adrenal Cortex↗
17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals.
The development of the human fetal adrenals starts in the 6th week gestational age and adrenal C19 steroid production becomes of major importance for the maintenance of the pregnancy. Therefore, in the present study, human fetal adrenals at 6 weeks of gestational age were immunostained for 17 alpha-hydroxylase, the key enzyme for the production of C19-steroids. In parallel, chromaffin cells were characterized by immunohistochemical staining for chromogranin A, the major soluble protein in adrenal chromaffin granules. Large 17 alpha-hydroxylase-immunoreactive cells were found in the center of the adrenal anlagen during the 6th week of gestation. At the same developmental stage, chromaffin cells with a neuronal-like appearance occurred in the paraortic area and started to invade the adrenal primordium. Our results show that, even at week 6 gestational age, when chromaffin cells start to enter the adrenal anlagen, human adrenals already contain differentiated, 17 alpha-hydroxylase immunoreactive cortical cells which were located to the center of the primordium.
Adrenal Glands↗
Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis.
Interleukin (IL)-6 is a potent activator of the human hypothalamicpituitary-adrenal axis. After chronic administration of IL-6 in humans, there is a substantial elevation of cortisol, whereas ACTH levels are blunted. Thus, we investigated whether IL-6 and/or the IL-6 receptor (IL-6R) are expressed in the human adrenal gland and whether IL-6 could cause the release of steroid hormones by a direct action on adrenal cells in primary culture. The expression of IL-6 and IL-6R was investigated with RT-PCR and immunohistochemistry, and the effects on human adrenal steroidogenesis were tested with IL-6 in vitro. To avoid effects mediated by macrophages, we depleted adrenal primary cultures from macrophages using specific mouse antihuman CD68 and sheep antimouse IgG conjugated magnetic beads. The results showed that 1): IL-6 and IL-6R are expressed in adrenal cell cultures, including all cell types and those depleted of macrophages; 2) IL-6R is mainly expressed in the zona reticularis and the inner zona fasciculata; positive signals from the zona glomerulosa and the medulla occurred in single cells; and 3) IL-6 regulates adrenal synthesis of mineralocorticoids, glucocorticoids, and androgens in vitro, dependent on time and dose, in the absence of macrophages. After 24 h, aldosterone secretion increased to 172 +/- 28% SEM, cortisol to 177 +/- 27% SEM, and dehydroepiandrosterone to 153 +/- 20% SEM of basal secretion. These findings, in combination with previous investigations, suggest that IL-6 exerts its acute action via the hypothalamus and the pituitary. In the adrenal gland, however, IL-6 seems to be a long-term regulator of stress response, integrating the responses of all cortical zones to stimuli from the immune and endocrine system.
Adrenal Glands↗
Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly.
The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10-1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 +/- 37% (mean +/- SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 +/- 134 vs. 410 +/- 157 nmol/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.
Adrenal Glands↗
Expression of interleukin-1 in human pheochromocytoma.
Cytokines and in particular interleukin 1 (IL-1) play a role in the micro-environment of various tumors. In addition, it is well established that IL-1 is a neurotrophic, angiogenetic and fibrogenetic factor. Using in situ hybridization we analyzed the expression of endogenous IL-1 in human pheochromocytoma (PCC). With the help of specific antibodies to B- and T-cells, macrophages, and neuroendocrine cell antigens, we characterized the distribution and localization of various cell types in human PCC. The combination of immunohistochemistry and in situ hybridization was eminently suited to defining the exact cellular source of IL-1 expression. In situ hybridization and immunostaining revealed that IL-1 mRNA was located primarily in the tumor cell itself. IL-1 may therefore constitute an important paracrine/autocrine factor in neuroendocrine tumors.
Adrenal Gland Neoplasms↗
Angiotensin II regulates both adrenocortical and adrenomedullary function in isolated perfused pig adrenals.
The effect of angiotensin II (ANG II) on all four zones of the adrenal gland was studied in preparations of isolated perfused porcine adrenals. The experimental design offered the possibility to analyze directly the actions of ANG II while preserving the structure of the gland. ANG II stimulated aldosterone, cortisol, and androstenedione release in a dose-dependent manner. At a final ANG II concentration of 10(-8) M aldosterone increased from 0.7 +/- 0.05 to 3.4 +/- 0.9 ng/ml, cortisol from 50 +/- 5 to 430 +/- 60 micrograms/l, and androstenedione from 1.4 +/- 0.2 to 4.4 +/- 0.8 ng/ml. In addition, ANG II provoked a release of adrenaline from 4.1 +/- 0.6 to 27.5 +/- 0.5 micrograms/ml and of noradrenaline from 5.5 +/- 1.1 to 36.0 +/- 8.7 micrograms/ml. Our results show that secretion of both adrenocortical steroids and adrenomedullary catecholamines can be evoked by ANG II. ANG II seems to influence not only the function of the zona glomerulosa but the function of the entire adrenal gland.
Adrenal Cortex↗
Cellular communication in the neuro-adrenocortical axis: role of vasoactive intestinal polypeptide (VIP).
It is well established now that adrenocortical function, besides being regulated through systemic factors, is influenced by intra-adrenal mechanisms. In this context paracrine influences between the sympathoadrenal system and the adrenal cortex play an important role. As a prerequisite for these interactions, adrenal medullary cells and cortical cells are highly interwoven as revealed by immunohistochemistry. The potential role of VIP in the regulation of human adrenal steroidogenesis was now investigated in human adrenal cells in primary culture. The primary cultures contained both, cortical and chromaffin cells which were found to be in close cellular contact as revealed by immunocytochemistry. VIP enhanced cortisol secretion from adrenal cells in a dose-dependent manner with a maximal effect at 10(-7) M. VIP stimulated the release of dehydroepiandrosterone (DHEA), testosterone, androstenedione, and aldosterone significantly. The addition of propranolol, a beta-adrenergic antagonist, to the incubation medium attenuated VIP-induced corticosteroid secretion. It is concluded that VIP is a paracrine messenger in the human adrenal that could regulate adrenocortical function at least in part via catecholamines released from the medulla.
Adrenal Cortex↗
Differential regulation of apoptosis in the normal human adrenal gland.
Analysis of apoptosis in the human adrenal appears to be of eminent importance in the understanding of adrenal structure, zonation, and function. In this study we investigated the programmed cell death of normal adrenal tissues on the basis of apoptotic index by the nonradioactive in situ end labeling of DNA fragments, proliferating cell nuclear antigen, (PCNA), CD95 (cluster of differentiation), major histocompatibility complex class II immunohistochemistry, and ultrastructural analysis. The highest apoptotic index was detected in the outermost zones of the adrenal cortex, mainly in the zona glomerulosa. A labeling index of 50.46 +/- 5.22% (mean +/- SEM) for zona glomerulosa, 9.36 +/- 1.68% for zona fasciculata, 3.90 +/- 0.78% for zona reticularis, and 7.37 +/- 1.62% for the zona medullaris was found. Immunohistochemistry was used to distinguish between apoptotic and S phase cells. Positive anti-PCNA staining occurred in the inner cortical zones, whereas anti-CD95 signals appeared throughout the whole cortex, albeit at a much weaker level. MHC class II expression, which is known to be associated with programmed cell death, was demonstrated in the inner cortical zone. The data showed that mechanisms of cell death other than necrosis occur in the adrenal. In conclusion, we found a differential regulation of cell death for each zone of the adrenal cortex; the old theories of adrenal zonation (migrational vs. zonal or transformation theory) may, in fact, correlate with each other.
Adrenal Glands↗
Human adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence for paracrine control of adrenal function.
Tumor necrosis factor (TNF) is gaining increasing importance in clinical medicine. It plays a role in the interaction of the immune system with the hypothalamic-pituitary-adrenal axis. In the present study various morphological methods, including immunohistochemistry, electron microscopy, and in situ hybridization were applied to characterize the localization and distribution of TNF in the human adrenal gland. Double immunostaining revealed an astonishing degree of intermingling of steroid-producing cells and chromaffin cells. Macrophages could be found in all regions of the adrenal gland, but particularly in the transition zone of cortex and medulla. The steroid-producing cells of the inner zone of the cortex express major histocompatibility complex class II molecules. On the ultrastructural level, immune cells, steroid cells, and catecholamine-producing cells were found in direct contact. The combination of immunohistochemistry and in situ hybridization was optimally suited to define the exact cellular source of TNF in the human adrenal. TNF is produced in macrophages, but above all in 17 alpha-hydroxylase-positive cells (steroid-producing cells) in the zona reticularis and medulla. No signal was found in chromaffin cells. TNF may induce major histocompatibility complex class II in human adrenal gland in a paracrine or autocrine manner. It is concluded that TNF may have an important role in normal human adrenal physiology.
Adrenal Cortex↗
Sympathoadrenal system and immune system in the regulation of adrenocortical function.
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Adrenal Cortex↗
The adrenal gland and ACTH.
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Adrenal Glands↗
IL-1 is expressed in human adrenal gland in vivo. Possible role in a local immune-adrenal axis.
IL-1 is an important mediator in the dialogue between the immune system and the hypothalamo-pituitary-adrenal axis. A direct influence of IL-1 upon adrenal steroidogenesis has been demonstrated in experimental animals. We therefore designed a study to see if IL-1 is expressed within the normal human adrenal gland. The combination of in situ hybridization and specific immunostaining to IL-1 beta was eminently suited to demonstrate both mRNA and protein production. The specific immunostaining of the different cells combined with in situ hybridization (IL-1) allowed us to identify the exact cellular source of IL-1. IL-1 mRNA occurred in the zona reticularis in 17 alpha-hydroxylase positive steroid cells surrounding the adrenomedullary cells. Some CD68+ macrophages in this zona showed a positive signal. A weak signal was seen to IL-1 mRNA in few chromaffin cells, while IL-1-like immunoreactivity was more frequent. We conclude that in the normal situation in man IL-1 is mainly expressed in specialized cortical cells. The occurrence of the major glucocorticoid inducing factor in the normal human adrenal gland itself provides evidence for an autocrine or paracrine reaction under physiological conditions.
Adrenal Glands↗
Plasma catecholamines in patients with Addison's disease.
BACKGROUND AND OBJECTIVE: Two endocrine tissues are present within the adrenal gland: the steroid producing cortical cells and the catecholamine producing chromaffin cells. Glucocorticoids occur in high concentrations in the adrenal medulla. In vitro, glucocorticoids have been shown to induce the enzyme phenyl-N-methyl-transferase which is necessary for the production of adrenaline in adrenal medullary cells. The purpose of this study was to evaluate the possible significance of a local glucocorticoid effect on adrenomedullary function. DESIGN: Plasma catecholamine levels were measured in patients with autoimmune Addison's disease where local production of corticosteroids is deficient in the presence of intact chromaffin tissue. MEASUREMENTS: Catecholamines were measured by high pressure liquid chromatography and ACTH, renin and adrenal steroids by radioimmunoassay. PATIENTS: Nineteen Addisonian patients (9 females, 10 males) were treated according to a standard regime with oral cortisone acetate (37.5 mg/day) and fludrocortisone (0.1 mg/day). All patients were clinically well. RESULTS: Mean plasma adrenaline in patients with Addison's disease was significantly reduced compared to a sex and age matched control group (males (n = 10) 143 +/- 36 pmol/l, controls (n = 27) 303 +/- 30 pmol/l, P < 0.01; females (n = 9) 77 +/- 25 pmol/l, controls (n = 27) 293 +/- 21 pmol, P < 0.001). The noradrenaline:adrenaline ratio was clearly higher in patients with Addison's disease (males 24 +/- 4, controls 9 +/- 1, P < 0.01; females 45 +/- 6, controls 9 +/- 1, P < 0.01). CONCLUSION: We conclude that the physiologically high local glucocorticoid concentration may be responsible for normal adrenaline production under basal conditions.
Addison Disease↗
Macrophages within the human adrenal gland.
There is increasing evidence for an immune-adrenal interaction in which macrophages may play an important role. However, few data are available with respect to a human intra-adrenal macrophage system. In this study, we have investigated the density, distribution and phenotype of human adrenal macrophages using monoclonal antibodies. Macrophages are localized in all zones of the adrenal gland. These cells exhibit the phenotype of the phagocytotic macrophage compartment (CD11c+, KiM8+). At the ultrastructural level, macrophages are frequently attached to the endothelial wall, but also lie in direct contact with cortical and chromaffin cells. This investigation reveals the cellular basis for the possible role of macrophages in the local immune-neuroendocrine axis.
Adrenal Glands↗
Sympathoadrenal regulation of adrenal androstenedione release.
The effects of epinephrine and of splanchnic nerve activation on adrenocortical androstenedione release were studied in intact isolated perfused pig adrenals with preserved nerve supply. In addition, long-term effects of epinephrine were characterized in bovine adrenocortical cells in primary culture. To investigate the contact zones of the androgen-producing cells of the zona reticularis with the catecholamine producing cells of the adrenal medulla, cortical cells were immunostained for cytochrome P450 side chain cleavage (P450SCC). Perfusion of the isolated adrenals with epinephrine (10(-7) to 10(-5) M) stimulated androstenedione release in a dose-dependent manner. At a concentration of 10(-6) M, epinephrine provoked an increase to 179.11 +/- 16.14% of basal secretion (p < 0.05). Electrical stimulation of the splanchnic nerves led to an increase to 151.5 +/- 9.24% of basal values (p < 0.05). Epinephrine (10(-6) M) reached 40% and activation of the splanchnic nerves 26% of the stimulatory effect of ACTH at a physiological concentration (10(-10) M). The alpha-agonist phenylephrine had no effect on androstenedione release. In cell cultures, epinephrine stimulated the release of androstenedione in a dose-dependent manner with an ED50 of 0.75 x 10(-6) M. The maximal effect was reached at 10(-5) M with 8.92 +/- 0.66 pmol androstenedione/dish/24 h; the basal secretion was 1.44 +/- 0.54 pmol/dish/24 h. The epinephrine-stimulated androstenedione release was abolished by the beta-adrenergic antagonist propranolol while the alpha-adrenergic antagonist phentolamine had no effect. Immunohistochemical staining of paraffin sections of bovine and porcine adrenals for P450SCC revealed that zona reticularis and zona medullaris are closely interwoven.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Glands↗