caa a22 4500 445885246 CHVBK 20180317145557.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s00011-011-0316-7 doi (NATIONALLICENCE)springer-10.1007/s00011-011-0316-7 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 [Elektronische Daten] [B. Gesser, M. Rasmussen, L. Raaby, C. Rosada, C. Johansen, R. Kjellerup, K. Kragballe, L. Iversen] 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 p90kDa 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. Springer Basel AG, 2011 DMF nationallicence MIF nationallicence RSK1 nationallicence MSK1 nationallicence CREB nationallicence Cox-2 nationallicence c-Jun nationallicence p53 nationallicence DMF : Dimethylfumarate nationallicence MIF : Macrophage migration inhibitory factor nationallicence ERK : Extracellular signal-regulated kinase nationallicence MSK1 : Mitogen- and stress-activated protein kinase 1 nationallicence RSK1 : p90kDa ribosomal S6 kinase 1 nationallicence Gesser B. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Rasmussen M. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Raaby L. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Rosada C. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Johansen C. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Kjellerup R. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Kragballe K. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Iversen L. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut Inflammation Research SP Birkhäuser Verlag Basel 60/7(2011-07-01), 643-653 1023-3830 60:7<643 2011 60 11 https://doi.org/10.1007/s00011-011-0316-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00011-011-0316-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gesser B. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Rasmussen M. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Raaby L. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Rosada C. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Johansen C. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Kjellerup R. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Kragballe K. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 700 1- Iversen L. Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000, Aarhus, Denmark aut NATIONALLICENCE 773 0- Inflammation Research SP Birkhäuser Verlag Basel 60/7(2011-07-01), 643-653 1023-3830 60:7<643 2011 60 11 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer