This study characterizes the mRNA profile of the IL-17 isoforms and receptors in psoriatic skin lesions. Furthermore, we demonstrate for the first time augmented protein levels of IL-17A, IL-17C and IL-17F in psoriatic skin lesions, indicating a possible role for IL-17C in addition to IL-17A and IL-17F in the pathogenesis of psoriasis.

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.

This study demonstrates for the first time that the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin. In addition, specific signalling pathways leading to this phosphorylation have been identified. Together, our data indicate an important role of STAT1 in the pathogenesis of psoriasis.

The mitogen-activated protein kinases (MAPKs) are known to play a key role in the regulation of cytokine expression in several cell types. MAPK signal-integrating kinase 1 (Mnk1) is a kinase activated through both the stress- and cytokine-activated p38 MAPK pathway and the classical extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. In this study, we demonstrate that in cultured normal human keratinocytes Mnk1 and its downstream target eukaryotic initiation factor 4E (eIF4E) are phosphorylated in a time-dependent manner in response to stimulation with anisomycin or interleukin (IL)-1beta. Both the stimuli are well-recognized activators of the p38 MAPK pathway. Furthermore, we show that the Mnk inhibitor CGP57380 is capable of inhibiting the phosphorylation of eIF4E in keratinocytes, and that the abolishment of eIF4E phosphorylation dramatically decreases the anisomycin-induced protein release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 as well as the IL-1beta-induced protein release of TNF-alpha. Therefore, we propose that Mnk1 might contribute to the expression of pro-inflammatory cytokines found in inflammatory skin diseases.

Our results indicate that the specific inhibitory effects of DMF on RSK1 and MSK1 activation together with the induction of p-c-Jun (S63) and p-p53 (S15) lead to the inhibition of keratinocyte proliferation, partly explaining the anti-psoriatic effect of DMF.