Interleukin-1ß inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.
Mol Cell Endocrinol
; 381(1-2): 46-55, 2013 Dec 05.
Article
em En
| MEDLINE
| ID: mdl-23891856
ABSTRACT
Interleukin-1ß (IL-1ß) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1ß on placental insulin signaling is unknown. We recently reported increased IL-1ß protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1ß inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1ß (10pg/ml) for 24h. IL-1ß increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor ß expression. Furthermore, IL-1ß inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1ß alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1ß treatment. Moreover, IL-1ß inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1ß inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1ß levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trofoblastos
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Sistema A de Transporte de Aminoácidos
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Interleucina-1beta
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Insulina
Limite:
Female
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Humans
Idioma:
En
Revista:
Mol Cell Endocrinol
Ano de publicação:
2013
Tipo de documento:
Article