Crosstalk in Inflammation: The Interplay of Glucocorticoid Receptor-Based Mechanisms and Kinases and Phosphatases

Abstract

Glucocorticoids (GCs) are steroidal ligands for the GC receptor (GR), which can function as a ligand-activated transcription factor. These steroidal ligands and derivatives thereof are the first line of treatment in a vast array of inflammatory diseases. However, due to the general surge of side effects associated with long-term use of GCs and the potential problem of GC resistance in some patients, the scientific world continues to search for a better understanding of the GC-mediated antiinflammatory mechanisms. The reversible phosphomodification of various mediators in the inflammatory process plays a key role in modulating and fine-tuning the sensitivity, longevity, and intensity of the inflammatory response. As such, the antiinflammatory GCs can modulate the activity and/or expression of various kinases and phosphatases, thus affecting the signaling efficacy toward the propagation of proinflammatory gene expression and proinflammatory gene mRNA stability. Conversely, phosphorylation of GR can affect GR ligand- and DNA-binding affinity, mobility, and cofactor recruitment, culminating in altered transactivation and transrepression capabilities of GR, and consequently leading to a modified antiinflammatory potential. Recently, new roles for kinases and phosphatases have been described in GR-based antiinflammatory mechanisms. Moreover, kinase inhibitors have become increasingly important as antiinflammatory tools, not only for research but also for therapeutic purposes. In light of these developments, we aim to illuminate the integrated interplay between GR signaling and its correlating kinases and phosphatases in the context of the clinically important combat of inflammation, giving attention to implications on GC-mediated side effects and therapy resistance.

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

“…The transcriptional effects are mediated via the Gc receptor (GR), which is a member of the nuclear hormone receptor family. Gcs bind GR, which then functions as a transcription factor to trigger genomic effects, however there is now evidence of faster effects, mediated non-genomically via membraneassociated receptors and their signalling cascades (Beck et al 2009, Revollo & Cidlowski 2009). The GR gene generates several different splice and translation protein variants all of which are modular proteins that contain three distinct functional regions: an N-terminal transactivation domain, a central DNA-binding domain and a C-terminal region that contains the hormone-binding site (Gross et al 2009).…”

“…Observations from transgenic animals that express a dimerisation-deficient mutation of the GR suggest that a proportion of the effects of Gcs are not modulated by dimerisation-dependent DNA interactions (Reichardt & Schütz 1998). Some of these effects can be explained by the modulation of cytoplasmic pathways via direct proteinprotein interactions as shown for example with JNK (Löwenberg et al 2008, Beck et al 2009). Gcs exert a number of rapid actions that are independent of the regulation of gene transcription.…”

“…Gcs exert a number of rapid actions that are independent of the regulation of gene transcription. Binding of Gcs to the GR stimulates phosphatidylinositol 3-kinase (PI3K) and the protein kinase AKT (Beck et al 2009) in some cells. These effects result in rapid changes in the cytoplasmic environment that can lead to endothelial nitric oxide synthase (eNOS) activation and nitric oxide-dependent vasorelaxation (Hafezi-Moghadam et al 2002) amongst other effects.…”

Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

“…GR can directly transactivate gene transcription by binding to a GRE in target gene promoters, and it can transrepress gene transcription by tethering other transcription factors (29,37). To further examine whether TNF␣ blocks GR function, we investigated in TNF␣-treated mice the hepatic expression of a typical GR-transactivated gene (Tsc22d3, which encodes GILZ) and a typical GR-transrepressed gene, il1␤.…”

The pro-adhesive and pro-survival effects of glucocorticoid in human ovarian cancer cells

“…An important stress hormone, glucocorticoids (GCs), can affect tumor biology not only by their immunosuppression and anti-inflammatory effects (Beck et al 2009), but also by changing the tumor microenvironment as well as playing a direct role in regulating proliferation, differentiation, invasion, and apoptosis of tumor cells. Moreover, GCs are also widely used as comedication in cancer therapy of solid malignant tumors because of their beneficial effectiveness in treatment-related edema, inflammation, pain, and electrolyte imbalance (Rutz 2002, Correspondence should be addressed to Jian Lu or Ning Hui Email lujian326@163.com or huning324@aliyun.com Rutz & Herr 2004).…”