The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases

Abstract

Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.

Cell-type specific impact of glucocorticoid receptor activation on the developing brain

“…Quantitative PCR analyses revealed that neither progenitor (SOX2, PAX6) nor neuronal cell markers (TUBB3, MAP2), nor the GR itself (NR3C1) were significantly Dex-reactive (Figure 2A-B; statistics in Table S3), suggesting that acute Dex treatment does not impact cell-type composition. This was contrary to transcripts known to be up-regulated by glucocorticoids: FKBP5 33 , SGK1 22 , TSC22D3 32 and ZBTB16 34 . Most of the dose-time combinations tested resulted in significant up-regulation of these genes, except for SGK1 (Figure 2A-B; statistics in Table S3).…”

The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells

“…GC analogues have been shown to promote apoptosis of leukemic cells and to trigger complex anti-inflammatory actions by targeting both the molecular and cellular components of the immune system [3, 4]. GCs induce apoptotic death of immature, developing thymocytes and also some groups of mature, activated T-cells [5].…”

An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment

“…The transactivation of multiple checkpoint receptors and IL-10 by GR and the effect of glucocorticoid signaling on the effector responses of CD8 + TILs were reminiscent of our recent observation that IL-27 regulates a gene module that includes checkpoint receptors (Tim-3, Lag3, Tigit) and IL-10 and suppresses the responses of CD8 + TILs (Chihara et al, 2018;Zhu et al, 2015). Interestingly, glucocorticoids have been shown to work in concert with TFs such as the STAT family (Petta et al, 2016) Figure S7a). Examination of differentially expressed genes across all three conditions relative to control showed some common as well as some distinct genes ( Figure S7b).…”