Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice

Abstract

TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.

TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile

“…TNF also induces GCR in cell systems, including the lung epithelial cell line A549 (26). In recent studies, we have shown that GR homodimerization is absolutely essential in sustaining a basal protection, as well as in mounting antiinflammatory protection by exogenous, pharmacological synthetic GCs, in a model of acute, lethal inflammation (10). The data underline the importance of direct gene regulation by GR dimers.…”

“…1F. Since most of the differentially regulated genes are up-regulated by Dex, and based on compelling evidence suggesting that dimer-dependent direct GR gene regulation exhibits marked antiinflammatory properties (5,10,28), we further focused on the effect of TNF on key points in the direct GR gene up-regulating pathway.…”

“…Besides this mechanism, GR can also influence gene expression by interacting with other transcription factors, such as AP1 and NF-κB (8), a process mainly performed by GR monomers. Finally, GR can also regulate gene expression by binding to several types of negative GRE elements (e.g., inverted repeat negative GREs) (9) in upstream regions of GC-responsive genes, such as Stat1, and inhibit their transcription (10). GC-mediated regulation of genes is associated with the recruitment of transcriptional coregulators, such as the p160 steroid receptor coactivator (SRC) family (11), and chromatin remodeling factors, as well as p300 histone acetyl transferase (12) and corepressors.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…As almost all vertebrate cells express glucocorticoid receptors (GRs) the effects of GCs are pleiotropic; however, T‐cell‐specific responses to GCs have been shown to be involved in T‐cell homeostasis, and regulatory T (Treg) cell‐specific GR deficiency was recently shown to impair Treg cell capacity to prevent the induction of disease in a mouse model of inflammatory bowel disease . In addition, a recent study of mice with diminished GR responses revealed an interferon‐specific gene signature in the gut that was abrogated by antibiotic treatment, indicating a role for the microbiota . While information regarding intestinal production of GCs continues to emerge, the stimuli involved and immune cell effects have yet to be fully elucidated.…”

“…78,79 In addition, a recent study of mice with diminished GR responses revealed an interferon-specific gene signature in the gut that was abrogated by antibiotic treatment, indicating a role for the microbiota. 80 While information regarding intestinal production of GCs continues to emerge, the stimuli involved and immune cell effects have yet to be fully elucidated. Similarly, although a monoamine neurotransmitter, serotonin is primarily produced in the intestines by enterochromaffin cells.…”