Extracellular signal-regulated protein kinase mediates interleukin 17 (IL-17)-induced IL-8 secretion in Helicobacter pylori-infected human gastric epithelial cells
Extracellular signal-regulated protein kinase mediates interleukin 17 (IL-17)-induced IL-8 secretion in Helicobacter pylori-infected human gastric epithelial cells
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DOI：
10.1128/iai.72.9.5019-5026.2004
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发表时间：
2004-09-01
影响因子：
3.1
通讯作者：
Luzza, F
中科院分区：
文献类型：
--
作者：
Sebkova, L;Pellicanò, A;Luzza, F
幽门螺杆菌诱导的粘膜炎症导致胃上皮细胞中白细胞介素17（IL-17）的大量产生，IL-17是IL-8的有效诱导剂。本研究的目的是研究IL-17调节人胃上皮细胞IL-8产生的信号通路。在IL-17刺激的MKN 28细胞和分离自H.通过蛋白质印迹法评估幽门定殖的胃粘膜。在IL-17刺激的MKN 28细胞中，还通过电泳迁移率变动分析评估了活化蛋白1（AP-1）、核因子（NF）-IL-6和NF-κ B的活化。通过逆转录-PCR和酶联免疫吸附测定（ELISA）评估用特异性MAP激酶抑制剂处理的IL-17刺激的MKN 28细胞和用中和IL-17抗体处理的胃活检培养物的IL-8产生。H.通过ELISA检测幽门螺杆菌感染患者对CagA的免疫球蛋白G应答。用IL-17处理MKN 28细胞引起细胞外信号调节蛋白激酶1/2（ERK 1/2）的激活，但不引起其他MAP激酶的激活，并且具有AP-1和NF-κ B激活以及IL-8合成的下游效应。阻断ERK 1/2活性抑制AP-1介导的IL-8诱导，但不抑制NF-κ B介导的IL-8诱导。ERK 1/2在H.与未感染的对照组相比，感染幽门螺杆菌的患者的IL-8水平较高，这与IL-8水平较高有关。这些影响在CagA血清阳性患者中比在血清阴性患者中更明显。在胃活检培养物中，加入中和IL-17抗体降低ERK 1/2活化，从而导致IL-8的显著抑制。In H.在幽门定殖的胃上皮细胞中，IL-17诱导的IL-8合成与ERK 1/2 MAP激酶的活化相关并且至少部分依赖于ERK 1/2 MAP激酶的活化。
Helicobacter pylori-induced mucosal inflammation results in high production of interleukin 17 (IL-17), a potent inducer of IL-8 in gastric epithelial cells. The aim of this study was to investigate signaling pathways by which IL-17 regulates IL-8 production in human gastric epithelial cells. Activation of mitogen-activated protein (MAP) kinases in both IL-17-stimulated MKN28 cells and epithelial cells isolated from H. pylori-colonized gastric mucosa was assessed by Western blotting. In IL-17-stimulated MKN28 cells the activation of activatior protein 1 (AP-1), nuclear factor (NF)-IL-6, and NF-kappaB was also assessed by electrophoretic mobility shift assay. IL-8 production was evaluated by reverse transcription-PCR and enzyme-linked immunosorbent assay (ELISA) both for IL-17-stimulated MKN28 cells treated with specific MAP kinase inhibitors and gastric biopsy cultures treated with a neutralizing IL-17 antibody. Serum from H. pylori-infected patients was tested for immunoglobulin G response to CagA by ELISA. Treatment of MKN28 cells with IL-17 caused activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) but not other MAP kinases and had the downstream effects of AP-1 and NF-kappaB activation and IL-8 synthesis. Blocking ERK 1/2 activity inhibited AP-1-mediated, but not NF-kappaB-mediated, IL-8 induction. Enhanced activation of ERK 1/2 was seen in gastric epithelial cells isolated from H. pylori-infected patients in comparison to uninfected controls, and this was associated with high IL-8. These effects were even more pronounced in patients seropositive for CagA than in seronegative ones. In gastric biopsy cultures, the addition of a neutralizing IL-17 antibody decreased ERK 1/2 activation, thus resulting in a significant inhibition of IL-8. In H. pylori-colonized gastric epithelial cells, IL-17-induced IL-8 synthesis is associated with and depends at least in part on the activation of ERK 1/2 MAP kinase.