Parthenolide inhibits ERK and AP-1 which are dysregulated and contribute to excessive IL-8 expression and secretion in cystic fibrosis cells
Parthenolide inhibits ERK and AP-1 which are dysregulated and contribute to excessive IL-8 expression and secretion in cystic fibrosis cells
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DOI：
10.1186/1476-9255-8-26
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发表时间：
2011-10-12
影响因子：
5.1
通讯作者：
Bonfield, Tracey L.
中科院分区：
文献类型：
--
作者：
Saadane, Aicha;Eastman, Jean;Bonfield, Tracey L.
背景：IL-8 过度分泌是囊性纤维化 (CF) 的特征。这归因于上皮细胞 I-kappa B 激酶和/或 NF kappa B 的过度激活。IL-8 的最大产量需要 3 个协作机制：1) 启动子从抑制中释放； 2) NF kappa B 和 AP-1 激活转录； 3) p38-MAPK 稳定 mRNA。关于 CF 中 MAPK 或 AP-1 对 IL-8 的调节知之甚少。方法：我们使用 3 细胞模型在体外研究了我们的假设。其中两个模型是具有缺陷与正常囊性纤维化跨膜电导调节器 (CFTR) 表达的转化细胞系：反义/有义转染细胞系和患者衍生的 IB3-1/S9。在第三系列研究中，我们研究了用 CFTR 功能抑制剂处理的原代尸检人气管上皮细胞。所有细胞系均用小白菊内酯预处理，然后用 TNF α 和/或 IL-1 β 刺激。 结果：响应 TNF α 和/或 IL-1 β 刺激，CF 型细胞中 IL-8 的产生和 mRNA 表达高于非 CF 对照细胞。这与 p38、ERK1/2 和 JNK 的磷酸化增强以及 AP-1 的激活增加有关。由于我们之前表明小白菊内酯抑制 CF 细胞过度产生 IL-8，因此我们评估了其对 MAPK 和 AP-1 激活的影响，并表明小白菊内酯抑制 ERK 和 AP-1 激活。使用荧光素酶启动子测定，我们的研究表明，小白菊内酯降低了 TNF α/IL-1 β 刺激的 CF 细胞中 IL-8 启动子的激活。结论：除了 NF kappa B MAPKs ERK 之外，JNK 和 p38 以及转录因子 AP-1 在 CF 上皮细胞中也失调。小白菊内酯抑制 NF kappa B 和 MAPK/AP-1 通路，从而抑制 IL-8 的产生。
Background: Excessive secretion of IL-8 characterizes cystic fibrosis (CF). This has been attributed to excessive activation of epithelial cell I-kappa B Kinase and/or NF kappa B. Maximum IL-8 production requires 3 cooperative mechanisms: 1) release of the promoter from repression; 2) activation of transcription by NF kappa B and AP-1; 3) stabilization of mRNA by p38-MAPK. Little is known about regulation of IL-8 by MAPKs or AP-1 in CF.Methods: We studied our hypothesis in vitro using 3-cellular models. Two of these models are transformed cell lines with defective versus normal cystic fibrosis transmembrane conductance regulator (CFTR) expression: an antisense/sense transfected cell line and the patient derived IB3-1/S9. In the third series of studies, we studied primary necropsy human tracheal epithelial cells treated with an inhibitor of CFTR function. All cell lines were pretreated with parthenolide and then stimulated with TNF alpha and/or IL-1 beta.Results: In response to stimulation with TNF alpha and/or IL-1 beta, IL-8 production and mRNA expression was greater in CF-type cells than in non-CF controls. This was associated with enhanced phosphorylation of p38, ERK1/2 and JNK and increased activation of AP-1. Since we previously showed that parthenolide inhibits excessive IL-8 production by CF cells, we evaluated its effects on MAPK and AP-1 activation and showed that parthenolide inhibited ERK and AP-1 activation. Using a luciferase promoter assay, our studies showed that parthenolide decreased activation of the IL-8 promoter in CF cells stimulated with TNF alpha/IL-1 beta.Conclusions: In addition to NF kappa B MAPKs ERK, JNK and p38 and the transcription factor AP-1 are also dysregulated in CF epithelial cells. Parthenolide inhibited both NF kappa B and MAPK/AP-1 pathways contributing to the inhibition of IL-8 production.