Interleukin 6 increases the in vitro expression of key proteins associated with steroidogenesis in the bovine adrenal zona fasciculata

McIlmoil, S.; Strickland, J.; Judd, Allan M.

doi:10.1016/j.domaniend.2015.10.003

Cited by 9 publications

(6 citation statements)

References 43 publications

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“…Although it is known that IL-6 down-regulates DAX-1 gene expression in bovine zona fasciculate cells (47), studies in different steroidogenic tissues have shown that TNF-α can increase the expression of DAX-1 protein (48). Indeed, a rapid increase in TNF-α levels in plasma has been observed shortly after LPS stimulation in the rat (34), and we have observed a rapid increase in TNF-α hnRNA and mRNA in this study.…”

Section: Il-6supporting

confidence: 43%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. T he hypothalamic-pituitary-adrenal (HPA) axis is a stressresponsive neuroendocrine system that controls circulating levels of the vital glucocorticoid (CORT) hormones corticosterone (in rodents) and cortisol (in humans). These are steroids synthesized by the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary in response to corticotrophin-releasing hormone (CRH) and arginine vasopressin released from hypothalamic paraventricular neurons. These neurons receive circadian inputs from the suprachiasmatic nucleus and are activated in response to stress. Via the bloodstream, CORT accesses target tissues where it mediates metabolic, cognitive, and immune responses. CORT also regulates its own production through negative feedback inhibition of ACTH and CRH secretion from the pituitary and hypothalamus, respectively. To mount an effective response to stress, CORT must be secreted rapidly by the adrenal glands. However, because of its lipophilic nature, CORT cannot be prestored in vesicles and must therefore be rapidly synthesized de novo in response to ACTH stimulation.Under basal, unstressed conditions, ACTH and CORT exhibit ultradian oscillations. Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3, 4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents). Under normal physiological conditions, CORT secretion is tightly correlated with ACTH (5). However, there are a number of conditions where a dynamic dissociation between these hormones occurs (reviewed in ref. 6). For example, there is evidence that proinflammatory cytokines released during inflammation can poten...

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Section: Il-6supporting

confidence: 43%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A surprising finding of our study is the biphasic change in DAX-1 hnRNA, mRNA, and protein observed in the LPS experiment. Although it is known that IL-6 down-regulates DAX-1 gene expression in bovine zona fasciculate cells (47), studies in different steroidogenic tissues have shown that TNF-α can increase the expression of DAX-1 protein (48). Indeed, a rapid increase in TNF-α levels in plasma has been observed shortly after LPS stimulation in the rat (34), and we have observed a rapid increase in TNF-α hnRNA and mRNA in this study.…”

Section: Tnf-supporting

confidence: 43%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga¹,

Zavala²,

Jj³

et al. 2018

ESPE

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“…Inflammation is known to increase throughout the body with age, and IL-6 has been implicated in the regulation of steroidogenic enzyme expression in the HPA axis ( 10 , 22 ). To determine whether IL-6 had a role in the age-related changes in enzyme activity and expression, we quantified mRNA expression and protein levels of IL-6 in the cortex of young, middle-aged, and old mice.…”

Section: Resultsmentioning

confidence: 99%

“…The expression patterns of a variety of steroidogenic enzymes have been established in cell types throughout the brain, however the regulation of their expression is poorly understood [11,31]. In the adrenal glands of the HPA axis, IL-6 has been shown to increase the expression of both 11β-hydroxylase and 21-Hydroxylase, leading to the increased production of CORT [10]. IL-6 is one of several cytokines known to be elevated in the brain with age and contributes to the age-associated increase in inflammation [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicate that interleukin 6 (IL-6), an inflammatory cytokine, increases with age and, in the adrenal cortex, upregulates the expression of two enzymes, 11β-hydroxylase and 21-hydroxylase, which convert PRG to CORT ( 10 ). These enzymes, as well as others that lead to AlloP synthesis, are found in the endoplasmic reticulum and are expressed throughout various cell types in the brain ( 11 ).…”

mentioning

confidence: 99%

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Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

Parks

Logan

Yeganeh

et al. 2020

Journal of Lipid Research

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Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter Allopregnanolone levels, an important neurosteroid in the brain. We assessed the levels and regulation of allopregnanolone and the effects of allopregnanolone supplementation on cognitive function in 4 month old and 24 month old male C57BL/6 mice. With age, the expression of enzymes involved in the allopregnanolone synthetic pathway were decreased and corticosterone synthesis increased. Supplementation of allopregnanolone improved cognitive function. Interestingly, IL-6 infusion in young animals significantly reduced the production of allopregnanolone compared to controls. Of note, inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein gp130 (sgp130), significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of allopregnanolone and increases corticosterone levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in allopregnanolone levels and an increase in corticosterone. Furthermore, our results indicate that allopregnanolone is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

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Interleukin 6 increases the in vitro expression of key proteins associated with steroidogenesis in the bovine adrenal zona fasciculata

Cited by 9 publications

References 43 publications

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

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