Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases.

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 versatile role of MSKs in transcriptional regulation.

Among the mitogen-activated protein kinase (MAPK) targets, MSKs (mitogen- and stress-activated protein kinases) comprise a particularly interesting protein family. Because MSKs can be activated by both extracellular-signal-regulated kinase and p38 MAPKs, they are activated by many physiological and pathological stimuli. About ten years after their original discovery, they have been recognized as versatile kinases regulating gene transcription at multiple levels.

Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: possible partners in the combat against inflammation.

In the combat against inflammation, glucocorticoids (GCs) are a widespread therapeutic. These ligands of the glucocorticoid receptor (GR) inhibit the transactivation of various transcription factors, including nuclear factor-kappaB (NF-kappaB), and alter the composition of the pro-inflammatory enhanceosome, culminating in the repression of pro-inflammatory gene expression. However, pharmacological usage of GCs in long-term treatment is burdened with a detrimental side-effect profile.

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

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-kappaB (NF-kappaB). In addition to the well described interaction-based mutual repression mechanism between the GR and NF-kappaB, 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-kappaB p65 transactivation and of concurrent histone H3 phosphorylation.

A fully dissociated compound of plant origin for inflammatory gene repression.

The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-kappaB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR.