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Tacrolimus abrogates TGF ‐β1‐induced type I collagen production in normal human fibroblasts through suppressing p38 MAPK signalling pathway: implications on treatment of chronic atopic dermatitis lesions
Author(s) -
Lan C.C.E.,
Fang A.H.,
Wu P.H.,
Wu C.S.
Publication year - 2014
Publication title -
journal of the european academy of dermatology and venereology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.655
H-Index - 107
eISSN - 1468-3083
pISSN - 0926-9959
DOI - 10.1111/jdv.12086
Subject(s) - tacrolimus , medicine , transforming growth factor , fibrosis , fibroblast , cytokine , dermis , atopic dermatitis , calcineurin , dermal fibroblast , mapk/erk pathway , immunology , pharmacology , pathology , signal transduction , cell culture , transplantation , biology , microbiology and biotechnology , genetics
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 ( FK 506) 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 m RNA or proteins in fibroblasts. Results Our results revealed that the increased expressions of transforming growth factor‐β receptor I ( TGF ‐β RI ) and TGF ‐β RII 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 (p38 MAPK ) expression stimulated by TGF ‐β1 was down‐regulated by tacrolimus. Moreover, the fibroblasts treated with p38 MAPK 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.