title: STAT1 expression and activation is increased in lesional psoriatic skin.
abstract: BACKGROUND
  The JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway is known to play an important role in many cellular processes including inflammation. The activation of STAT1 is dependent on tyrosine 701 and serine 727 phosphorylation, which leads to the formation of the STAT dimer and modulation of STAT1 activity, respectively.
  
  
  OBJECTIVE
  To determine STAT1 expression and activation in psoriatic skin.
  
  
  METHODS
  Biopsies were collected from patients with psoriasis. mRNA expression was evaluated by quantitative polymerase chain reaction, whereas the protein and phosphorylation level of STAT1 were evaluated by Western blotting. STAT1 localization was determined by immunofluorescence analysis and STAT1-induced transcriptional activity was analysed in cultured human keratinocytes using a reporter assay.
  
  
  RESULTS
  The expression of STAT1 was demonstrated to be significantly increased at both mRNA and protein level in lesional psoriatic skin. In addition, the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) was significantly increased in lesional compared with nonlesional psoriatic skin. Luciferase assays showed a significant induction of the STAT1-induced transcriptional activity when cultured human keratinocytes were stimulated with either interferon (IFN)-α or IFN-γ. STAT1(Ser727) phosphorylation induced by IFN-α, IFN-γ or ultraviolet B was mediated by a protein kinase C (PKC)-δ- and p38 mitogen-activated protein kinase-dependent mechanism in human keratinocytes, whereas IFN-α-induced STAT1(Tyr701) phosphorylation was mediated by a PKC-δ-dependent mechanism.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, P.P. Oerumsgade 11, Aarhus C DK-8000, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Hald
authors.forename: R M
authors.initials: RM
authors.lastname: Andrés
authors.forename: M L
authors.initials: ML
authors.lastname: Salskov-Iversen
authors.forename: R B
authors.initials: RB
authors.lastname: Kjellerup
authors.forename: L
authors.initials: L
authors.lastname: Iversen
authors.forename: C
authors.initials: C
authors.lastname: Johansen
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000502:physiology; D010766:Phosphorylation; D011565:Psoriasis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007372:Interferons; D048051:p38 Mitogen-Activated Protein Kinases