title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000 Aarhus, Denmark. gesser@post11.tele.dk
authors.forename: B
authors.initials: B
authors.lastname: Gesser
authors.forename: M K
authors.initials: MK
authors.lastname: Rasmussen
authors.forename: L
authors.initials: L
authors.lastname: Raaby
authors.forename: C
authors.initials: C
authors.lastname: Rosada
authors.forename: C
authors.initials: C
authors.lastname: Johansen
authors.forename: R B
authors.initials: RB
authors.lastname: Kjellerup
authors.forename: K
authors.initials: K
authors.lastname: Kragballe
authors.forename: L
authors.initials: L
authors.lastname: Iversen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003879:Dermatologic Agents / Q000494:pharmacology; D000069462:Dimethyl Fumarate; D005419:Flavonoids / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D011565:Psoriasis / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D003879:Dermatologic Agents; D005419:Flavonoids; D005650:Fumarates; D008263:Macrophage Migration-Inhibitory Factors; D016159:Tumor Suppressor Protein p53; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048031:JNK Mitogen-Activated Protein Kinases; D000069462:Dimethyl Fumarate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one