Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

Newton, Robert; Shah, Suharsh; Altonsy, Mohammed O.; Gerber, A.N.

doi:10.1074/jbc.r117.777318

Cited by 78 publications

(73 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is because of the feedback loop that leads to reduction in the gain on GR synthesis due to lower ACTH stimulated cortisol release and subsequent reduction in the anti-inflammatory response (See Figure S7). This results in increased pro-inflammatory milieu that acts to further upregulate HPA axis in an attempt to restore homeostasis, however at the cost of dysregulated immune response 52 . Our sample revealed a significant and robust positive causal association of cortisol suppression with hs-CRP ( =1.808, p=0.009, q=0.038, τ 2 =0.315) and IL6 ( =1.234, p=0.026, q=0.091, τ 2 =0.255); and a trend level reduction in IC 50 levels (p=0.08).…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi

Mellon

Flory

et al. 2018

Preprint

View full text Add to dashboard Cite

PTSD is associated with metabolic comorbidities; however it is not clear how the neuroendocrine disturbances affect metabolism. To analyze this we employed a systems biological approach using an integrated mathematical model of metabolism, HPA axis and inflammation. We combined the metabolomics, neuroendocrine, clinical lab and cytokine data from combat-exposed veterans with and without PTSD, to characterize the differences in regulatory effects. We used the pattern of fold change in metabolites representing pathway level differences as reference for metabolic control analysis (MCA) using the model. MCA revealed parameters constituting the HPA axis, inflammation and GPCR pathway that yielded metabolic dysfunction consistent with PTSD. To support this, we performed causal analysis between regulatory components and the significantly different metabolites in our sample. Causal inference revealed that the changes in glucocorticoid receptor sensitivity were mechanistically associated with metabolic dysfunction and the effects were jointly mediated by insulin resistance, inflammation, oxidative stress and energy deficit.Post-traumatic stress disorder (PTSD) is defined by a complex set of criteria including intrusive reminders, fear memories, emotional distress, hypervigilance and exaggerated startle responses that develop and persist after an exposure to trauma 1 . Multiple physiological systems at the neuronal, metabolic, inflammatory, genomic and epigenomic levels are known to be affected in PTSD 2,3 . Previous studies from our PTSD Systems Biology consortium reported associations between PTSD and insulin resistance 4 , inflammation 5 , reduced mitochondrial copy number 6 , and lower methylation of the glucocorticoid receptor (NR3C1) gene 7 in the same cohorts assessed in the present study. The data from animal models and humans with PTSD reveal association between inflammation and metabolic syndrome 8 . Analysis of metabolomics have revealed metabolic changes consistent with dysregulation in mitochondrial functioning in PTSD 9 . Another study reported differences in the mitochondrial DNA (SNPs) located in NADH dehydrogenase and ATP synthase genes in PTSD 10 . Variants of mitochondrial genes and dysregulation of their associated networks have been reported in the postmortem brains of patients with PTSD 11 .One of the major physiological regulatory axes, Hypothalamic-Pituitary-Adrenal (HPA) axis is implicated in the pathogenesis of PTSD and associated metabolic disorders 12,13 . The HPA axis relays stress signals from the brain to peripheral parts through the release of glucocorticoids (GCs) and catecholamine hormones. GCs orchestrate the activities of several physiological functions through glucocorticoid receptor (GRs) signaling. Therefore, the feedback sensitivity of GC signaling among other factors can influence downstream effects of stress exposure. GR signaling is regulated at transcriptional and epigenetic levels and is dysregulated in HPA axis associated disorders 14 . Recent studies have highlighted the asso...

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi

Mellon

Flory

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Asthma is a complex disease with diverse underlying pathological mechanisms with both the young and the elderly (Hasegawa et al, 2017;Li et al, 2016;Lotvall et al, 2011). Bronchial hyperresponsiveness, airway remodeling (Movassagh et al, 2016), abnormal hormone secretion (Newton et al, 2017), and chronic airway inflammation (Parulekar, Diamant & Hanania, 2017) are some of the major clinical features of asthma.…”

Section: Introductionmentioning

confidence: 99%

Key genes and co-expression modules involved in asthma pathogenesis

Huang

Liu

Zuo

et al. 2020

PeerJ

View full text Add to dashboard Cite

Machine learning and weighted gene co-expression network analysis (WGCNA) have been widely used due to its well-known accuracy in the biological field. However, due to the nature of a gene’s multiple functions, it is challenging to locate the exact genes involved in complex diseases such as asthma. In this study, we combined machine learning and WGCNA in order to analyze the gene expression data of asthma for better understanding of associated pathogenesis. Specifically, the role of machine learning is assigned to screen out the key genes in the asthma development, while the role of WGCNA is to set up gene co-expression network. Our results indicated that hormone secretion regulation, airway remodeling, and negative immune regulation, were all regulated by critical gene modules associated with pathogenesis of asthma progression. Overall, the method employed in this study helped identify key genes in asthma and their roles in the asthma pathogenesis.

show abstract

“…Mechanisms underpinning GR-mediated gene repression are less well understood. Although protein products resulting from GR-induced gene expression, such as TSC22D3 and DUSP1, are known to indirectly contribute to glucocorticoid-mediated transcriptional repression (Auphan et al 1995;Ronchetti et al 2015;Newton et al 2017), direct repressive effects of GR on inflammatory transcription factors, such as NF-kB, have long been viewed as principally responsible for the potent repressive effects of glucocorticoids on cytokine expression (Cruz-Topete and Cidlowski 2015; Vandewalle et al 2018). Such primary repressive effects have been variably attributed to protein-protein tethering of monomeric GR to DNA-associated inflammatory transcription factors, commonly referred to as transrepression (Ratman et al 2013;De Bosscher et al 2014), and also to protein-DNA interactions between GR and so-called negative glucocorticoid response elements (nGREs) found within regulatory regions for inflammatory genes (King et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

Sasse

Gruca

Allen

et al. 2019

Preprint

View full text Add to dashboard Cite

The glucocorticoid receptor (GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements remains controversial.Here, using Global Run-on Sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 minutes. Many repressed regulatory regions reside within 'hyper-ChIPable' genomic regions that are subject to nonspecific interactions with some antibodies. When this was accounted for, we determined that transcriptional repression occurs without local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and enhancer-reporter assays. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions.Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.3

show abstract

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

Cited by 78 publications

References 100 publications

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Key genes and co-expression modules involved in asthma pathogenesis

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

Contact Info

Product

Resources

About