首页> 外文期刊>American Journal of Physiology >ERK1/2 and Egr-1 contribute to increased TNF-alpha production in rat Kupffer cells after chronic ethanol feeding.
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ERK1/2 and Egr-1 contribute to increased TNF-alpha production in rat Kupffer cells after chronic ethanol feeding.

机译:慢性乙醇喂养后,ERK1 / 2和Egr-1有助于大鼠Kupffer细胞中TNF-α的产生增加。

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摘要

Activation of Kupffer cells by lipopolysaccharide (LPS) is a critical step in the pathogenesis of alcoholic liver disease. Kupffer cells isolated from rats fed ethanol in their diet for 4 wk accumulated 4.3-fold more tumor necrosis factor (TNF)-alpha in response to LPS compared with pair-fed rats. In contrast, LPS-stimulated interleukin (IL)-1 accumulation was 50% lower after ethanol feeding. LPS-stimulated TNF-alpha mRNA accumulation was twofold higher after ethanol feeding, whereas IL-1beta mRNA accumulation was blunted. To understand the mechanisms for this differential response, we investigated the effects of ethanol on LPS-dependent signal transduction. Chronic ethanol feeding increased LPS-stimulated extracellular receptor-activated kinases 1/2 (ERK1/2) activation. Activation of ERK1/2 was required for maximal increases in TNF-alpha and IL-1beta mRNA and was associated with increased binding of early growth response-1 (Egr-1) to the TNF-alpha promoter after ethanol feeding. In contrast, ethanol feeding completely abrogated activation of nuclear factor-kappaB DNA-binding activity by LPS and had no effect on AP-1 binding. Together, these data suggest that enhanced activation of ERK1/2 and Egr-1 contributes to increased TNF-alpha production after chronic ethanol feeding.
机译:脂多糖(LPS)激活Kupffer细胞是酒精性肝病发病机理中的关键步骤。从成对饲喂乙醇的大鼠中分离出的库普弗细胞,在4周内对LPS的累积的肿瘤坏死因子(TNF)-α比成对喂养的大鼠多4.3倍。相反,喂食乙醇后,LPS刺激的白介素(IL)-1积累降低了50%。喂食乙醇后,LPS刺激的TNF-αmRNA积累增加了两倍,而IL-1beta mRNA的积累则变得钝了。为了了解这种差异反应的机制,我们研究了乙醇对LPS依赖信号转导的影响。长期喂食乙醇会增加LPS刺激的细胞外受体激活的激酶1/2(ERK1 / 2)的激活。最大限度地增加TNF-α和IL-1beta mRNA的表达需要激活ERK1 / 2,并且与乙醇喂养后早期生长应答1(Egr-1)与TNF-alpha启动子的结合增加有关。相反,乙醇喂养完全消除了LPS对核因子-κBDNA结合活性的激活,并且对AP-1结合没有影响。在一起,这些数据表明,慢性乙醇喂养后,增强的ERK1 / 2和Egr-1激活有助于增加TNF-α的产生。

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