Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-κB inhibition

Abstract

Glucocorticoids are widely used anti-inflammatory and immunomodulatory agents, of which the action mechanism is mainly based on interference of hormone-activated glucocorticoid receptor (GR) with the activity of transcription factors, such as nuclear factor-jB (NF-jB). In addition to the well described interaction-based mutual repression mechanism between the GR and NF-jB, additional mechanisms are at play, which help to explain the efficacy of glucocorticoid-mediated gene repression. In this respect, we found that glucocorticoids counteract the recruitment of activated Mitogen-and Stress-activated protein Kinase-1 (MSK1) at inflammatory gene promoters resulting in the inhibition of NF-jB p65 transactivation and of concurrent histone H3 phosphorylation. Additionally, we observed that activated GR can trigger redistribution of nuclear MSK1 to the cytoplasm through a CRM1-dependent export mechanism, as a result of an interaction between liganded GR and activated MSK1. These findings unveil a novel aspect within the GR-mediated NF-jB-targeting anti-inflammatory mechanism.

Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

“…2F). MSK1 also promotes inflammatory gene transcription by phosphorylating NF-B itself, allowing it to recruit coactivators, and by phosphorylating histone H3, allowing it to induce chromatin loosening (15). The time courses and concentration-response relationships of all these CSE-induced responses were very similar, pointing to a broadly coordinated proinflammatory program in lung epithelial cells.…”

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…7, Point 3). Initially identified as a nuclear kinase, MSK1 was later shown to present in the cytosol as well (26). MSK1 phosphorylates p65 at serine 276, and this phosphorylation was much reduced in MSK1/2-deficient mouse embryonic fibroblasts (36).…”

Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes

“…GR and p65 or JUN, an AP1 subunit, are suggested to physically interact and mutually antagonize each other's transcriptional activity (Konig et al 1992;Ray and Prefontaine 1994;Gottlicher et al 1998;Adcock et al 1999). In addition, other mechanisms have been suggested for the anti-inflammatory effects of GR, such as modulation of chromatin environment (Ito et al 2000;Tsaprouni et al 2002;Beck et al 2008) and competition for a limiting amount of cofactors, such as the acetyltransferases CREBBP and EP300 (Kamei et al 1996). In principle, multiple layers of regulation seem to be involved in the crosstalk of GR and NFKB or AP1; however, the mechanism and extent of crosstalk has remained unresolved.…”