Interleukin-6 increases the expression of key proteins associated with steroidogenesis in human NCI-H295R adrenocortical cells

Strickland, J.; McIlmoil, S.; Williams, Byron; Seager, Dennis C.; Porter, James P.; Judd, Allan M.

doi:10.1016/j.steroids.2016.12.014

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…P45011bOH (Strickland et al, 2017). The mechanism by which IL-6 probably stimulates the secretion of DHEAS, that is, by increasing the expression of StAR and enzymes related to androgen synthesis has been proved in our previous research.…”

Section: Discussionmentioning

confidence: 79%

Interleukin‐6 increases adrenal androgen release by regulating the expression of steroidogenic proteins in NCI‐H295R cells

Xian

Zhang

Peng

et al. 2020

Journal Cellular Physiology

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The purpose of this study was to investigate the potential mechanism of interleukin‐6 (IL‐6) on the stimulation of excessive androgen secretion in human NCI‐H295R adrenocortical cells. We performed transcriptome sequencing of cancer and paracancerous tissues obtained from functional adrenal cortical adenomas. The secretion of dehydroepiandrosterone sulfate (DHEAS) in NCI‐H295R cells was detected by a chemiluminescence assay. The expression of messenger RNA (mRNA) was detected by real‐time polymerase chain reaction and that of protein was detected by western blotting. The expression of secretogranin II (SCG2) and IL‐6 were significantly increased in cancer tissues. Upregulation of mRNA and protein levels of AKR1C3, CYP11A, CYP17A1, 3βHSD, and SULT2A1 was observed after stimulation with IL‐6. IL‐6 could also increase the expression of StAR mRNA and proteins. Our results suggest that IL‐6 can promote androgen secretion by regulating the expression of genes related to androgen pathways.

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Section: Discussionmentioning

confidence: 79%

Interleukin‐6 increases adrenal androgen release by regulating the expression of steroidogenic proteins in NCI‐H295R cells

Xian

Zhang

Peng

et al. 2020

Journal Cellular Physiology

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“…Boonen et al have reported that inflammatory cytokines, including TNF-α and IL-6, are positively correlated with cortisol production, and that cortisol clearance is reduced by the suppression of 11β-HSD2 activity, which catalyzes the conversion of cortisol to inactivated cortisone in critically ill patients [4]. TNF-α, IL-1, and IL-6 have been reported to enhance steroidogenesis in the human adrenocortical cell line NCI-H295R [21][22][23]. In contrast, TNF-α has been observed to suppress the activity of 11β-HSD2 in the porcine renal epithelial cell line LLC-PK 1 [24], and the mRNA expression of key proinflammatory cytokines (TNF-α, IL-1β, and IL-6) has been shown to be upregulated but that of 11β-HSD2 downregulated in the colon tissue from patients with inflammatory bowel disease [25].…”

Section: Discussionmentioning

confidence: 99%

ACTH-cortisol dissociation in patients with Kawasaki disease: a retrospective study

Aso

Satoh

2021

Endocr J

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ACTH-cortisol dissociation is recognized in patients with critical illnesses. Cytokines, including tumor necrosis factor-α and interleukin-6 induce hypercortisolemia by enhancing the ACTH-independent synthesis and secretion of cortisol and by reducing cortisol breakdown. Subsequently, hypercortisolemia suppresses ACTH secretion by negative feedback inhibition. ACTH-cortisol dissociation in patients with systemic inflammatory diseases has not been reported. Here, we examined whether ACTH-cortisol dissociation is recognized in patients with Kawasaki disease (KD) associated with hypercytokinemia, as well as the possible cytokine involvement in ACTH-cortisol dissociation, retrospectively. The levels of serum cortisol, plasma ACTH, and cytokine-induced proteins, i.e., plasma C-reactive protein (CRP), serum ferritin, and urinary β2-microglobulin (U-β2MG), in 232 patients with KD were measured at diagnosis. Quartile groups based on cytokineinduced protein levels were formed (Q1, Q2, Q3, and Q4). We found a low median plasma ACTH [median (range): 8.9 (<2.0-332.0) pg/mL] but a high median serum cortisol level [median (range): 25.8 (1.4-99.8) μg/dL] in the entire study population. The median serum cortisol levels were significantly higher in the CRP-Q4, ferritin-Q4, and U-β2MG-Q4 groups than in the CRP-Q1, ferritin-Q2, and U-β2MG-Q1 groups, respectively (p < 0.01; p < 0.01; p < 0.001). The median plasma ACTH levels were significantly lower in the CRP-Q4 and ferritin-Q4 groups than in the CRP-Q1 and ferritin-Q1 groups, respectively (p < 0.001; p < 0.001). ACTH-cortisol dissociation was identified in patients with KD. Our findings suggest that inflammatory cytokines are involved in ACTH-independent hypercortisolemia in patients with KD. ACTH-cortisol dissociation in other systemic inflammatory diseases needs further investigation.

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“…This demonstration, along with the activating effects of IL-1β on the HPA axis [2] and the increased production of the cytokine in the context of inflammatory chronic diseases, prompted us to search for a possible effect of it on adrenal steroidogenesis. By using the cell line NCI-H295R as a model, we performed dose-response assays employing various concentrations of IL-1β falling within the range seen in plasma from TB patients [4] and above, at different treatment time points (6,12,24, and 48 h). However, treatment with IL-1β alone resulted in no changes in the production of cortisol, DHEA, or DHEA-S (data not shown), and adrenal cells treated with Fsk showed a clearly increased production of these steroids (Fig.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Unlike acute stress, wherein ACTH production in the anterior pituitary is the primary regulator of cortisol release, protracted inflammation-associated chronic stress reveals a poor correlation between ACTH and glucocorticoid levels, implying that additional factors may be involved in glucocorticoid release or availability. Putative factors in this regard may comprise a decreased clearance of glucocorticoids and mediators acting locally, like cytokines [6]. The adrenal gland is permanently exposed to circulating cytokines, and there is also a local production.…”

Section: Introductionmentioning

confidence: 99%

Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As

Santucci

Stampone

Silva

et al. 2020

Neuroimmunomodulation

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Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on them. The miRNA profile was modified by IL-1β treatment to an extent which bears some relationship with the regulatory mechanisms underlying adrenal steroid production. Since orphan nuclear receptors NR4As have emerged as potential key factors for coordinating inflammatory and metabolic responses, cell expression studies were also carried out to show an NR4As transcript augmentation following IL-1β treatment. Discussion/Conclusions: The subtle increase in adrenal steroid production in response to IL-1β stimulation without any modification in the transcription of the steroidogenic enzymes analyzed suggests an additional inflammatory/anti-inflammatory loop, wherein NR4As receptors may participate. Besides its physiological role, this process might be implied in pathological states accompanied by an unbalanced immune-endocrine relationship.

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Interleukin-6 increases the expression of key proteins associated with steroidogenesis in human NCI-H295R adrenocortical cells

Cited by 12 publications

References 45 publications

Interleukin‐6 increases adrenal androgen release by regulating the expression of steroidogenic proteins in NCI‐H295R cells

Interleukin‐6 increases adrenal androgen release by regulating the expression of steroidogenic proteins in NCI‐H295R cells

ACTH-cortisol dissociation in patients with Kawasaki disease: a retrospective study

Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As

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