Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.
Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.
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DOI：
10.1016/j.mce.2013.07.013
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发表时间：
2013-12-05
影响因子：
4.1
通讯作者：
Powell TL
中科院分区：
文献类型：
--
作者：
Aye IL;Jansson T;Powell TL
白细胞介素-1 β（IL-1β）可促进肝脏和骨骼肌等组织的胰岛素抵抗，但其对胎盘胰岛素信号传导的影响尚不清楚。我们最近报道了肥胖母亲胎盘中IL-1β蛋白表达增加，这可能有助于胰岛素抵抗。在这项研究中，我们测试的假设，IL-1β抑制胰岛素信号转导，并阻止胰岛素刺激的氨基酸转运培养的原代人滋养层细胞（PHT）。用生理浓度的IL-1β（10 pg/ml）处理从足月胎盘分离的培养的滋养层24小时。IL-1β增加胰岛素受体底物-1（IRS-1）Ser 307（抑制性）的磷酸化，降低IRS-1总蛋白丰度，但不影响胰岛素受体β表达。此外，IL-1β抑制胰岛素刺激的IRS-1（Tyr 612，激活位点）和Akt（Thr 308）的磷酸化，并阻止胰岛素刺激的PI 3 K/p85和Grb 2蛋白表达的增加。IL-1β单独刺激cRaf（Ser 338）、MEK（Ser 221）和Erk 1/2（Thr 202/Tyr 204）磷酸化。IL-1β治疗也激活了与胰岛素抵抗相关的炎症途径核因子kappa B和c-Jun N末端激酶。此外，IL-1β抑制胰岛素刺激的系统A，但不抑制系统L氨基酸摄取，表明胰岛素信号传导功能受损。总之，IL-1β通过抑制IRS-1信号传导抑制胰岛素信号传导途径，并阻止胰岛素刺激的系统A转运，从而促进培养的PHT细胞中的胰岛素抵抗。这些结果表明，导致全身母体或胎盘IL-1β水平升高的疾病可能会减弱母体胰岛素对胎盘功能的影响，从而影响胎儿生长。
Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β 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-1β (10 pg/ml) for 24 hours. IL-1β 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 β expression. Furthermore, IL-1β 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-1β 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-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β 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-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth.
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