Ultraviolet A1 phototherapy decreases inhibitory SMAD7 gene expression in localized scleroderma

Abstract

Localized scleroderma (LS) is a connective skin disease with marked sclerosis of the skin as the most prominent feature. Transforming growth factor beta (TGF-beta) plays a central role in the pathogenesis of sclerotic skin diseases. Recently, special attention was contributed to a family of transcription factor proteins involved in TGF-beta signal transduction from cell surface to the nucleus, the so-called SMADs. Ultraviolet (UV) irradiation has been reported to alter TGF-beta/SMAD pathway in human skin. We sought to investigate the effects of UVA1 on the gene and protein expressions of the TGF-beta/SMAD pathway in LS. UVA1 phototherapy was performed in eight LS patients five times weekly for 8 weeks resulting in a total of 40 treatment sessions (single dose 50 J/cm(2), cumulative dose 2,000 J/cm(2)). TGF-beta1, SMAD3, SMAD4, and SMAD7 mRNA expressions were determined by semiquantitative real-time reverse transcription polymerase chain reaction in lesional and unaffected skin of patients with LS. Additionally, immunohistochemical staining was performed in lesional skin before and after irradiation. Skin status markedly improved in all patients, resulting in a significant reduction of the clinical score from baseline to the end of treatment. Inhibitory SMAD7 mRNA was significantly higher in lesional skin as compared to unaffected skin, and significantly decreased after UVA1 phototherapy. In contrast, SMAD7 mRNA levels remained unchanged in irradiated, healthy skin after UVA1. Both TGF-beta and SMAD3 mRNA levels decreased after UVA1, whereas SMAD4 mRNA increased. However, changes in TGF-beta, SMAD3, and SMAD4 mRNA after UVA1 did not reach statistical significance. Immunohistochemical investigation did not reveal significant changes in the protein expression of SMADs after UVA1. Similar to scleroderma, SMAD7-mediated negative regulation seems to be impaired in LS. UVA1 phototherapy demonstrated the alteration of SMAD7 gene expression in LS, as SMAD7 mRNA levels normalized after UVA1. The pathogenetic relevance of SMAD7 levels with respect to clinical improvement needs further investigation.