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Tacrolimus abrogates TGF-β1-induced type I collagen production in normal human fibroblasts through suppressing p38MAPK signalling pathway: implications on treatment of chronic atopic dermatitis lesions.
MedLine Citation:
PMID:  23301526     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Atopic dermatitis (AD) is a commonly encountered inflammatory skin disease. Although acute lesions of acute AD are characterized by intense inflammation, the hallmarks of chronic AD lesions include lichenified fibrosis and thickening of the upper dermis. The increased expression of transforming growth factor beta 1 (TGF-β1), a well-known fibrogenic cytokine, is observed in chronic AD lesions. Tacrolimus (FK506) ointment has been reported to be effective for treating AD as well as some TGF-β1-induced fibrotic diseases. OBJECTIVES: To evaluate the effect of tacrolimus on TGF-β1-stimulated cultured normal human dermal fibroblasts and explore the potential signalling pathways involved. METHODS: Fibroblasts cultured from healthy adult human foreskins were treated with TGF-β1 with or without tacrolimus. The impact on cell viability and proliferation were assessed by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and BrdU incorporation assay respectively. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to evaluate the relevant expressions of mRNA or proteins in fibroblasts. RESULTS: Our results revealed that the increased expressions of transforming growth factor-β receptor I (TGF-βRI) and TGF-βRII in TGF-β1-treated fibroblasts were suppressed by tacrolimus treatment. In addition, tacrolimus significantly inhibited fibroblast proliferation enhanced by TGF-β1. TGF-β1 increased type I collagen production, and this enhancing effect was suppressed by tacrolimus. The down-regulation of MMP-1 and up-regulation of TIMP-1 induced by TGF-β1 were reversed by tacrolimus. The increase in phosphorylated p38 mitogen-activated protein kinase (p38MAPK) expression stimulated by TGF-β1 was down-regulated by tacrolimus. Moreover, the fibroblasts treated with p38MAPK inhibitor significantly reduced type I collagen expression induced by TGF-β1. CONCLUSIONS: The present results demonstrated that tacrolimus significantly inhibited physiological functions of fibroblasts enhanced by TGF-β1 in vitro. Clinically, we propose that topical tacrolimus may not only reduce AD recurrence but also ameliorate dermal fibrosis often seen in chronic AD lesions.
Authors:
C-C E Lan; A-H Fang; P-H Wu; C-S Wu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-10
Journal Detail:
Title:  Journal of the European Academy of Dermatology and Venereology : JEADV     Volume:  -     ISSN:  1468-3083     ISO Abbreviation:  J Eur Acad Dermatol Venereol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9216037     Medline TA:  J Eur Acad Dermatol Venereol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.
Affiliation:
Department of Dermatology, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
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