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Dimethylfumarate inhibits MIF-induced proliferation of keratinocytes by inhibiting MSK1 and RSK1 activation and by inducing nuclear p-c-Jun (S63) and p-p53 (S15) expression

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Abstract

Objective

Dimethylfumarate (DMF) is used in the treatment of psoriasis. Macrophage migration inhibitory factor (MIF) is elevated in patients with severe psoriasis. We studied the effect of DMF on the MIF-induced activation of the mitogen- and stress-activated kinase 1 (MSK1) and p90 kDa ribosomal S6 kinase (RSK1) signaling pathways which regulate the proliferation of human keratinocytes via transcription factors.

Methods

The effects of DMF on the MIF-induced activation of MSK1, RSK1, cAMP-responsive element-binding protein (CREB), Cox-2 and c-Jun, JunB and p53 were studied by Western blotting using phospho-specific antibodies.

Results

DMF inhibited the MIF-induced phosphorylation of MSK1, RSK1, CREB and JunB, and reduced Cox-2 expression and the proliferation of cultured human keratinocytes. The expression of p-p53 (S15) was induced simultaneously with the inhibition of Cox-2. Addition of DMF before MIF induced nuclear expression of p-c-Jun (S63) and c-Jun. Transfection with small interfering MSK1 and RSK1 RNA before MIF incubation stimulated p-p53 (S15) and nuclear p-c-Jun (S63) similarly to DMF.

Conclusion

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.

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Abbreviations

DMF:

Dimethylfumarate

MIF:

Macrophage migration inhibitory factor

ERK:

Extracellular signal-regulated kinase

MSK1:

Mitogen- and stress-activated protein kinase 1

RSK1:

p90 kDa ribosomal S6 kinase 1

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Acknowledgement

This work was supported by research grants from the Danish Psoriasis Foundation, the Novo Nordisk Foundation, Aage Bang Foundation DK and Gangsted Foundation DK.

Conflict of interest

The authors state no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark

    B. Gesser, M. K. Rasmussen, L. Raaby, C. Rosada, C. Johansen, R. B. Kjellerup, K. Kragballe & L. Iversen

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  1. B. Gesser
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  2. M. K. Rasmussen
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  3. L. Raaby
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  7. K. Kragballe
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  8. L. Iversen
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Correspondence to B. Gesser.

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Responsible editor: Liwu Li.

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Gesser, B., Rasmussen, M.K., Raaby, L. et al. Dimethylfumarate inhibits MIF-induced proliferation of keratinocytes by inhibiting MSK1 and RSK1 activation and by inducing nuclear p-c-Jun (S63) and p-p53 (S15) expression. Inflamm. Res. 60, 643–653 (2011). https://doi.org/10.1007/s00011-011-0316-7

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  • DOI: https://doi.org/10.1007/s00011-011-0316-7

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