Abnormal regulation of fibronectin production by fibroblasts in psoriasis

Summary 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. Objectives 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 , FGFR 2, 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 ( MEK 1), AKT 1/2, STAT 1 and STAT 3. Results The expression of α5 integrin, EDA + FN , KGF and its receptor FGFR 2 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 FGFR 2‐ III c splice variant. STAT 1 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 STAT 1 in healthy and lesional skin, similarly to a previous report. However, in the nonlesional skin STAT 1 activation was absent in tissues far away from lesions. Conclusions The production of FN and EDA + FN by fibroblasts and the signalling of STAT 1 are abnormally regulated in psoriatic nonlesional skin.