title: Abnormal regulation of fibronectin production by fibroblasts in psoriasis.
abstract: BACKGROUND
  Data indicate that in psoriasis, abnormalities are already present in nonlesional skin. Transforming growth factor-β and keratinocyte growth factor (KGF), together with fibronectin and α5β1 integrin, were suggested to play a crucial role in the pathogenesis of psoriasis by influencing inflammation and keratinocyte hyperproliferation.
  
  
  OBJECTIVE
  To investigate the expression of KGF, fibroblast growth factor receptor (FGFR)2, fibronectin (FN) and extra domain A (EDA)-positive FN in healthy and nonlesional psoriatic skin, and to study the effect of KGF on the regulation of FN and EDA(+) FN production by fibroblasts.
  
  
  METHODS
  Healthy, nonlesional psoriatic skin and lesional psoriatic skin were immunostained for α5 integrin, KGF, FGFR2, EDA(+) FN and signal transducer and activator of transcription (STAT)1. KGF-treated cell cultures were analysed for FN and EDA(+) FN mRNA and protein by real-time reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. The major downstream signalling of KGF was investigated by blocking experiments using inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK1), AKT1/2, STAT1 and STAT3.
  
  
  RESULTS
  The expression of α5 integrin, EDA(+) FN, KGF and its receptor FGFR2 is elevated in psoriatic nonlesional skin compared with healthy skin. KGF mildly induced EDA(+) FN, but not FN expression in healthy fibroblasts through MAPK signalling. Fibroblasts express the FGFR2-IIIc splice variant. STAT1 negatively regulates both FN and EDA(+) FN expression in healthy fibroblasts, and this regulation is compromised in fibroblasts derived from nonlesional psoriatic dermis. We detected active STAT1 in healthy and lesional skin, similarly to a previous report. However, in the nonlesional skin STAT1 activation was absent in tissues far away from lesions.
  
  
  CONCLUSIONS
  The production of FN and EDA(+) FN by fibroblasts and the signalling of STAT1 are abnormally regulated in psoriatic nonlesional skin.
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Gubán
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Vas
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Balog
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Manczinger
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Bebes
authors.affiliation: MTA-SZTE Dermatological Research Group, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Groma
authors.affiliation: MTA-SZTE Dermatological Research Group, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.|Department of Medical Genetics, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Széll
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.|MTA-SZTE Dermatological Research Group, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Kemény
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.|MTA-SZTE Dermatological Research Group, University of Szeged, Korányi fasor 6, H-6720, Szeged, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Bata-Csörgő
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D051523:Fibroblast Growth Factor 7 / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis* / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008544:Melanocytes / Q000378:metabolism; D008875:Middle Aged; D011565:Psoriasis / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism; D055815:Young Adult
chemical_list: C067625:FN1 protein, human; D005353:Fibronectins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D051523:Fibroblast Growth Factor 7; D051497:Receptor, Fibroblast Growth Factor, Type 2