Dimethylfumarate Specifically Inhibits the Mitogen and Stress-Activated Kinases 1 and 2 (MSK1/2): Possible Role for its Anti-Psoriatic Effect

Abstract

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-kappaB, is activated in lesional psoriatic skin. The purpose of this study was to investigate the effect of fumaric acid esters (FAEs) on the p38 MAPK and the downstream kinases mitogen- and stress-activated protein kinase (MSK)1 and 2 in cultured human keratinocytes. Cell cultures were incubated with dimethylfumarate (DMF), methylhydrogenfumarate (MHF), or fumaric acid (FA) and then stimulated with IL-1beta before kinase activation was determined by Western blotting. A significant inhibition of both MSK1 and 2 activations was seen after preincubation with DMF and stimulation with IL-1beta, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-kappaB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1beta resulted in a significant decrease in NF-kappaB binding to the IL-8 kappaB and the IL-20 kappaB-binding sites as well as a subsequent decrease in IL-8 and IL-20 mRNA expression. Our results suggest that DMF specifically inhibits MSK1 and 2 activations and subsequently inhibits NF-kappaB-induced gene-transcriptions, which are believed to be important in the pathogenesis of psoriasis. These effects of DMF explain the anti-psoriatic effect of FAEs.

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 2). Our observation is in conflict with a study published by Gesser et al (47) where DMF inhibits MSK1 without affecting p38 or ERK1/2. However, different cell types and different stimuli may explain the difference we observed.…”

IκBα glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES

“…Furthermore, MSK-1 phosphorylation at the Ser360 and Thr581 phosphorylation sites, which are directly targeted by p38 or ERK MAPK [28], were not affected by DMF treatment. These findings are in agreement with another study in keratinocytes, showing that DMF inhibited MSK-1 phosphorylation at Ser376 independently of p38 or ERK MAPK [21]. MKP-1, an endogenous inhibitor of MAPK, can be upregulated by reduced GSH levels [29] and, besides inhibiting MAPK p38 and ERK in ASMCs [23], it was reported to dephosphorylate histone H3 at Ser10 [30].…”

“…Previously, it was shown that DMF inhibits the phosphorylation of MSK-1 at Ser376, resulting in reduced phosphorylation of downstream CREB (cyclic adenosine monophosphate response element binding) and NF-kB p65 [7,21]. MSK-1 also phosphorylates histone H3 at Ser10 [20], which increases the accessibility of NF-kB binding sites within different promoters [19].…”

“…Histone H3 phosphorylation at Ser10 occurs in the promoters of NF-kB-regulated cytokines, such as RANTES [18], and has been shown to increase the accessibility of NF-kB binding sides [19]. Mitogen-and stress-activated protein kinase (MSK)-1 phosphorylates histone H3 at Ser10 [20], and MSK-1 is inhibited by DMF in ASMCs and keratinocytes [7,21]. Therefore, inhibition of MSK-1-mediated histone H3 phosphorylation by DMF may contribute to its inhibitory effect on NF-kBdependent chemokine secretion.…”

The Role of p38 MAPK in Rheumatic Diseases

“…Western blotting analysis revealed a consistent and significant increase in phosphorylated MSK1 (Ser376) in lesional psoriatic skin [78,79]. Cultured human keratinocytes incubated with anisomycin or IL-1β resulted in the phosphorylation of both p38 MAPK and MSK1 (Ser376) whereas MSK1 (Ser376) phosphorylation was inhibited by pre-incubation with p38 inhibitors or dimethylfumarate [80]. In addition, transcription factors, such as cAMP/calcium responsive element binding protein (CREB) associated with cellular proliferation gene expression, are also phosphorylated in psoriatic skin [81].…”