IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-ß receptor on hepatic stellate cells in a JNK-dependent manner.
J Immunol
; 193(8): 3925-33, 2014 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-25210118
ABSTRACT
Activation of hepatic stellate cells (HSCs) is a key event in the initiation of liver fibrosis, characterized by enhanced extracellular matrix production and altered degradation. Activation of HSCs can be modulated by cytokines produced by immune cells. Recent reports have implicated the proinflammatory cytokine IL-17A in liver fibrosis progression. We hypothesized that IL-17A may enhance activation of HSCs and induction of the fibrogenic signals in these cells. The human HSC line LX2 and primary human HSCs were stimulated with increasing doses of IL-17A and compared with TGF-ß- and PBS-treated cells as positive and negative controls, respectively. IL-17A alone did not induce activation of HSCs. However, IL-17A sensitized HSCs to the action of suboptimal doses of TGF-ß as confirmed by strong induction of α-smooth muscle actin, collagen type I (COL1A1), and tissue inhibitor of matrix metalloproteinase I gene expression and protein production. IL-17A specifically upregulated the cell surface expression of TGF-ßRII following stimulation. Pretreatment of HSCs with IL-17A enhanced signaling through TGF-ßRII as observed by increased phosphorylation of SMAD2/3 in response to stimulation with suboptimal doses of TGF-ß. This enhanced TGF-ß response of HSCs induced by IL-17A was JNK-dependent. Our results suggest a novel profibrotic function for IL-17A by enhancing the response of HSCs to TGF-ß through activation of the JNK pathway. IL-17A acts through upregulation and stabilization of TGF-ßRII, leading to increased SMAD2/3 signaling. These findings represent a novel example of cooperative signaling between an immune cytokine and a fibrogenic receptor.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Fator de Crescimento Transformador beta
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Receptores de Fatores de Crescimento Transformadores beta
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Interleucina-17
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Proteínas Quinases JNK Ativadas por Mitógeno
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Células Estreladas do Fígado
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Cirrose Hepática
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article