MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells:: involvement of nuclear factor-κB and activator protein-1
MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells:: involvement of nuclear factor-κB and activator protein-1
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DOI：
10.1111/j.1365-2567.2008.02806.x
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发表时间：
2008-08-01
期刊：
影响因子：
6.4
通讯作者：
Bravo-Cuellar, Alejandro
中科院分区：
文献类型：
--
作者：
Ortiz-Lazareno, Pablo C.;Hernandez-Flores, Georgina;Bravo-Cuellar, Alejandro
响应炎症刺激，单核细胞/巨噬细胞分泌大量促炎细胞因子肿瘤坏死因子-α (TNF-α)、白介素-1 β (IL-1 β) 和 IL-6。炎症过程和先天免疫反应与多种转录因子的激活有关，例如核因子κB（NF-κB）和激活蛋白1（AP-1）。蛋白酶体是一种多聚体蛋白酶复合物，在多种细胞功能中发挥着至关重要的作用，包括调节 NF-kappa B 等转录因子。在这项研究中，我们使用脂多糖 (LPS) 和佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 刺激的人单核细胞系 U937 作为模型，研究蛋白酶体抑制剂 MG132 对蛋白酶体释放的体外影响。 TNF-α、IL-1β 和 IL-6 及其膜和可溶性受体 TNF-R1、IL-1R1 和 IL-6R 的表达。我们还分析了 MG132 对 NF-kappa B 和 AP-1 激活以及 I kappa B 分子的影响。 MG132 显着抑制这些促炎细胞因子的分泌。 MG132 增加 U937 细胞中可溶性受体 TNF-R1 和 IL-1R1 的释放，并降低其细胞表面表达。 MG132 还增加 IL-6R 细胞表面表达并减少其释放。蛋白酶体抑制还导致 LPS+PMA 诱导的 AP-1 激活增加和 LPS+PMA 诱导的 I kappa B 降解减弱，从而消除 NF-kappa B 激活。我们的实验强烈表明蛋白酶体是调节促炎细胞因子及其受体的重要因素。
In response to inflammatory stimuli, monocytes/macrophages secrete greater quantities of the proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-6. The inflammatory process and the innate immune response are related to the activation of several transcription factors, such as nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1). The proteasome is a multimeric protease complex, which plays a vital role in several cellular functions, including the regulation of transcription factors like NF-kappa B. In this study, we used the human monocyte cell line U937 stimulated with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) as a model to investigate the in vitro effects of MG132, a proteasome inhibitor, on the release of TNF-alpha, IL-1 beta and IL-6 and on the expression of their membrane and soluble receptors TNF-R1, IL-1R1 and IL-6R. We also analysed the effects of MG132 on the activation of NF-kappa B and AP-1 and on the I kappa B molecule. MG132 significantly inhibited the secretion of those proinflammatory cytokines. MG132 increased the release of the soluble receptors TNF-R1 and IL-1R1 from U937 cells and decreased their cell-surface expression. MG132 also increased IL-6R cell-surface expression and decreased its release. Proteasome inhibition also led to an increase in LPS+PMA-induced AP-1 activation and the attenuation of LPS+PMA-induced I kappa B degradation, resulting in the abolition of NF-kappa B activation. Our experiments strongly suggest that the proteasome is an important factor in the regulation of proinflammatory cytokines and their receptors.