Anti-fibrotic activity and enhanced interleukin-6 production by hepatic stellate cells in response to imatinib mesylate.
Liver Int
; 32(6): 1008-17, 2012 Jul.
Article
em En
| MEDLINE
| ID: mdl-22507133
ABSTRACT
OBJECTIVE:
To examine imatinib mesylate's effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti-fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase inhibitor indicated for treatment of chronic myelogenous leukaemia and GI stromal tumours.DESIGN:
Because imatinib inhibits ß-PDGFR signalling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets in a human stellate cell line (LX-2) using cDNA microarray. METHODS ANDRESULTS:
Imatinib inhibited proliferation of LX-2 cells (0.5-10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated ß-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen α(1) (I), alpha smooth muscle actin, ß-PDGFR, transforming growth factor ß receptor type 1, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2. In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide (TAA) led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib.CONCLUSIONS:
These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Pirimidinas
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Interleucina-6
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Inibidores de Proteínas Quinases
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Células Estreladas do Fígado
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Cirrose Hepática Experimental
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Liver Int
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos