Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes:: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C
Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes:: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C
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DOI：
10.1046/j.1471-4159.2001.00652.x
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发表时间：
2001-12-01
影响因子：
4.7
通讯作者：
Hüll, M
中科院分区：
文献类型：
--
作者：
Fiebich, BL;Schleicher, S;Hüll, M
环氧化酶-2 （COX-2）的表达和前列腺素E2 （PGE(2)）的合成以及白细胞介素-6 （IL-6）等细胞因子都被认为在不同的脑部疾病如hiv -痴呆、朊病毒病、中风和阿尔茨海默病中传播神经病理。在本报告中，我们发现PGE(2)刺激了U373 MG人星形胶质瘤细胞和原代大鼠星形胶质细胞中IL-6的释放。PGE(2)诱导的细胞内cAMP形成通过前列腺素E受体2 （EP2）介导，但抑制cAMP形成和蛋白激酶A或阻断EP1/EP2受体不影响PGE(2)诱导的IL-6合成。这表明cAMP途径不是PGE(2)诱导的导致IL-6释放的信号转导级联的一部分。EP3/ ep1受体激动剂磺胺酮未能诱导IL-6释放，提示ep4样受体参与其中。PGE(2)激活p38丝裂原活化激酶（p38 MAPK）和蛋白激酶C （PKC）。PGE(2)诱导的IL-6合成被p38 MAPK （SB202190）和PKC （GF203190X）特异性抑制剂抑制。尽管到目前为止，EP受体很少与p38 MAPK或PKC激活相关联，但这些结果表明，PGE(2)通过独立于cAMP的ep4样受体激活PKC和p38 MAPK，从而通过ep4样受体诱导IL-6。
The expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E2 (PGE(2)) as well as of cytokines such as interleukin-6 (IL-6) have all been suggested to propagate neuropathology in different brain disorders such as HIV-dementia, prion diseases, stroke and Alzheimer's disease. In this report, we show that PGE(2)-stimulated IL-6 release in U373 MG human astroglioma cells and primary rat astrocytes. PGE(2)-induced intracellular cAMP formation was mediated via prostaglandin E receptor 2 (EP2), but inhibition of cAMP formation and protein kinase A or blockade of EP1/EP2 receptors did not affect PGE(2)-induced IL-6 synthesis. This indicates that the cAMP pathway is not part of PGE(2)-induced signal transduction cascade leading to IL-6 release. The EP3/EP1-receptor agonist sulprostone failed to induce IL-6 release, suggesting an involvement of EP4-like receptors. PGE(2)-activated p38 mitogen-activated kinase (p38 MAPK) and protein kinase C (PKC). PGE(2)-induced IL-6 synthesis was inhibited by specific inhibitors of p38 MAPK (SB202190) and PKC (GF203190X). Although, up to now, EP receptors have only rarely been linked to p38 MAPK or PKC activation, these results suggest that PGE(2) induces IL-6 via an EP4-like receptor by the activation of PKC and p38 MAPK via an EP4-like receptor independently of cAMP.