Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis.
Ann Rheum Dis
; 71(5): 737-45, 2012 May.
Article
em En
| MEDLINE
| ID: mdl-22258492
ABSTRACT
OBJECTIVES:
The hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach.METHODS:
Phosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis.RESULTS:
Transforming growth factor beta (TGFß) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis.CONCLUSIONS:
These data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFß and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Escleroderma Sistêmico
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Dermatopatias
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Fibrose
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Marcação de Genes
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Proteínas Quinases JNK Ativadas por Mitógeno
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article