FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: implication for new therapeutic approach.
C-S Wu, P-H Wu, A-H Fang, C-C E Lan
Department of Medical Laboratory Science and Biotechnology, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
The British journal of dermatology 2012 SepKeloid is a unique proliferative disorder of fibroblasts resulting from derailment of the typical wound healing process. Due to lack of animal models for therapeutic testing, treatment of keloids remains a clinical challenge. Transforming growth factor (TGF)-β1-related signalling plays a key role in keloid formation. As tacrolimus (FK506) has been reported to inhibit the effects of TGF-β1 on cultured fibroblasts, we hypothesized that FK506 may be useful in treating keloids. To explore the effects of FK506 on TGF-β1-stimulated keloid fibroblasts (KFs) in terms of proliferation, migration and collagen production and to investigate the regulatory pathways involved. Fibroblasts derived from keloids were treated with TGF-β1 with or without FK506. Relevant assays including 5-bromo-2'-deoxyuridine incorporation assay, in vitro scratch assay, reverse transcription-polymerase chain reaction (PCR), quantitative PCR and Western blotting were performed. The proliferation and migration of KFs were significantly higher than those of normal fibroblasts. FK506 markedly inhibited KF proliferation, migration and collagen production enhanced by TGF-β1. The increase in TGF-β receptor I and II expression in TGF-β1-treated KFs was suppressed by FK506 treatment. TGF-β1 increased the phosphorylation of Smad2/3 and Smad4 in KFs, and this enhancing effect was abrogated by FK506. In addition, FK506 significantly increased the expression of Smad7 which was suppressed by TGF-β1 treatment. Our results demonstrate that FK506 effectively blocks the TGF-β/Smad signalling pathway in KFs by downregulation of TGF-β receptors and suggest that FK506 may be included in the armamentarium for treating keloids. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.
Citation
C-S Wu, P-H Wu, A-H Fang, C-C E Lan. FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: implication for new therapeutic approach. The British journal of dermatology. 2012 Sep;167(3):532-41
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PMID: 22540338
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