Apremilast interferes with the TGFß1-induced transition of human skin fibroblasts into profibrotic myofibroblasts: in vitro study.
Rheumatology (Oxford)
; 59(12): 3927-3938, 2020 12 01.
Article
em En
| MEDLINE
| ID: mdl-32725130
ABSTRACT
OBJECTIVES:
Fibroblast-to-myofibroblast transition and extracellular matrix overproduction represent progressive events in chronic inflammatory and fibrotic diseases, in which TGFß1 is one of the key mediators. Phosphodiesterase 4 (PDE4) acts as a proinflammatory enzyme through the degradation of cyclic adenosine monophosphate and it is overexpressed in skin fibroblasts. The study investigated how apremilast (a PDE4 inhibitor) interferes with the intracellular signalling pathways responsible for the TGFß1-induced fibroblast-to-myofibroblast transition and profibrotic extracellular matrix protein synthesis.METHODS:
Cultured human skin fibroblasts were stimulated with TGFß1 (10 ng/ml) alone or combined with apremilast (1 and 10 µM) for 4, 16 and 24 h. Other aliquots of the same cells were previously stimulated with TGFß1 and then treated with apremilast (1 and 10 µM) for 4, 16 and 24 h, always under stimulation with TGFß1. Gene and protein expression of αSMA, type I collagen (COL1) and fibronectin were evaluated, together with the activation of small mothers against decapentaplegic 2 and 3 (Smad2/3) and extracellular signal-regulated kinase (Erk1/2) proteins.RESULTS:
Apremilast reduced the TGFß1-induced increase in αSMA, COL1 and fibronectin gene expression at 4 and 16 h, and protein synthesis at 24 h of treatment in cultured fibroblasts, even for cells already differentiated into myofibroblasts by way of a previous stimulation with TGFß1. Apremilast inhibited the TGFß1-induced Smad2/3 and Erk1/2 phosphorylation at 15 and 30 min.CONCLUSION:
Apremilast seems to inhibit in vitro the fibroblast-to-myofibroblast transition and the profibrotic activity induced by TGFß1 in cultured human skin fibroblasts by downregulating Smad2/3 and Erk1/2 intracellular signalling pathways.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pele
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Talidomida
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Diferenciação Celular
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Anti-Inflamatórios não Esteroides
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Fator de Crescimento Transformador beta1
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Miofibroblastos
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Fibroblastos
Limite:
Female
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article