Mitogen- and stress-activated protein kinase 2 and cyclic AMP response element binding protein are activated in lesional psoriatic epidermis.
The activity of the p38 mitogen-activated protein kinases (MAPKs) is increased in lesional psoriatic skin, supporting a possible role of these kinases in the pathogenesis of psoriasis. Recently, increased focal activation of the downstream target mitogen- and stress-activated protein kinase 1 (MSK1) was demonstrated in psoriatic epidermis. The purpose of this study is to investigate MSK2 and the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in psoriatic skin and in cultured normal human keratinocytes. In lesional psoriatic skin, significantly increased MSK2 (Ser196) and CREB (Ser133) activation was demonstrated by phospho blotting. Immunofluorescence staining of phosphorylated MSK2 (Ser196) revealed colocalization with phosphorylated MSK1 (Thr 581) in the epidermis. Keratinocyte cultures stimulated with anisomycin and IL-1beta showed increased MSK2 (Ser196) and CREB (Ser133) phosphorylation. Such activation was abolished during preincubation with a p38 inhibitor. Keratinocytes transfected with small interfering RNA showed a stronger decrease in CREB phosphorylation in MSK1/2 double-transfected cells than in MSK1 and MSK2 single-transfected cells. This study demonstrate for the first time the expression of MSK2 in keratinocytes and increased MSK2 and CREB activation in lesional psoriatic skin. Our results indicate that the p38-MAPK/MSK1/MSK2 and CREB signalling pathway may play a role in the pathogenesis of psoriasis.
Funding
Anne T
AT
Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, Aarhus C, Denmark.
Johansen
Claus
C
Kragballe
Knud
K
Iversen
Lars
L
D000328:Adult; D002478:Cells, Cultured; D003429:Cross Reactions; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004817:Epidermis / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D010766:Phosphorylation; D011565:Psoriasis / Q000209:etiology* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases