NF-κB-dependent IL-8 induction by prostaglandin E2 receptors EP1 and EP4
NF-κB-dependent IL-8 induction by prostaglandin E2 receptors EP1 and EP4
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DOI：
10.1111/j.1476-5381.2012.02182.x
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发表时间：
2013-02-01
影响因子：
7.3
通讯作者：
Pueschel, G. P.
中科院分区：
文献类型：
--
作者：
Neuschaefer-Rube, F.;Pathe-Neuschaefer-Rube, A.;Pueschel, G. P.
背景和目的：最近的研究表明PGE 2在趋化因子IL-8的表达中起作用。PGE 2信号通过四个不同的GPCR，EP 1-EP 4。在过表达EP 1（HEK-EP 1）、EP 4（HEK-EP 4）或两种受体（HEK-EP 1 + EP 4）的HEK 293细胞中研究了EP 1和EP 4受体对IL-8诱导的作用。实验方法IL-8 mRNA和蛋白诱导及IL-8启动子和NF-？在表达EP的HEK细胞中评估B活化。关键结果在HEK-EP 1和HEK-EP 1 + EP 4细胞中，而不是在HEK或HEK-EP 4细胞中，PGE 2激活IL-8启动子并诱导IL-8 mRNA和蛋白质合成。用EP 1特异性激动剂刺激HEK-EP 1 + EP 4细胞激活IL-8启动子并诱导IL-8 mRNA和蛋白质，而特异性EP 4激动剂既不激活IL-8启动子也不诱导IL-8 mRNA和蛋白质合成。用两种激动剂同时刺激HEK-EP 1 + EP 4细胞激活IL-8启动子并诱导IL-8 mRNA达到与PGE 2相同的程度。在HEK-EP 1 + EP 4细胞中，抑制I？B激酶。PGE 2激活NF-？HEK-EP 1、HEK-EP 4和HEK-EP 1 + EP 4细胞中的B。在HEK-EP 1 + EP 4细胞，同时激活两种受体需要最大的PGE 2诱导的NF-？B激活。PGE 2刺激的NF-？B的激活由EP 1被PLC，钙信号和Src激酶的抑制剂阻断，而由EP 4诱导的激活仅由Src激酶抑制钝化。结论和影响这些研究结果表明，PGE 2介导的NF-？通过同时刺激EP 1和EP 4受体的B活化诱导最大的IL-8启动子活化和IL-8 mRNA和蛋白诱导。
Background and Purpose Recent studies suggested a role for PGE2 in the expression of the chemokine IL-8. PGE2 signals via four different GPCRs, EP1-EP4. The role of EP1 and EP4 receptors for IL-8 induction was studied in HEK293 cells, overexpressing EP1 (HEK-EP1), EP4 (HEK-EP4) or both receptors (HEK-EP1 + EP4). Experimental Approach IL-8 mRNA and protein induction and IL-8 promoter and NF-?B activation were assessed in EP expressing HEK cells. Key Results In HEK-EP1 and HEK-EP1 + EP4 but not HEK or HEK-EP4 cells, PGE2 activated the IL-8 promoter and induced IL-8 mRNA and protein synthesis. Stimulation of HEK-EP1 + EP4 cells with an EP1-specific agonist activated IL-8 promoter and induced IL-8 mRNA and protein, whereas a specific EP4 agonist neither activated the IL-8 promoter nor induced IL-8 mRNA and protein synthesis. Simultaneous stimulation of HEK- EP1 + EP4 cells with both agonists activated IL-8 promoter and induced IL-8 mRNA to the same extent as PGE2. In HEK-EP1 + EP4 cells, PGE2-mediated IL-8 promoter activation and IL-8 mRNA induction were blunted by inhibition of I?B kinase. PGE2 activated NF-?B in HEK-EP1, HEK-EP4 and HEK-EP1 + EP4 cells. In HEK-EP1 + EP4 cells, simultaneous activation of both receptors was needed for maximal PGE2-induced NF-?B activation. PGE2-stimulated NF-?B activation by EP1 was blocked by inhibitors of PLC, calcium-signalling and Src-kinase, whereas that induced by EP4 was only blunted by Src-kinase inhibition. Conclusions and Implications These findings suggest that PGE2-mediated NF-?B activation by simultaneous stimulation of EP1 and EP4 receptors induces maximal IL-8 promoter activation and IL-8 mRNA and protein induction.