Perfluorooctane sulfonate mediates microglial activation and secretion of TNF-alpha through Ca2+-dependent PKC-NF-kappa B signaling
Perfluorooctane sulfonate mediates microglial activation and secretion of TNF-alpha through Ca2+-dependent PKC-NF-kappa B signaling
复制标题
全氟辛烷磺酸通过 Ca2 依赖性 PKC-NF-kappa B 信号传导介导小胶质细胞活化和 TNF-α 分泌
DOI：
10.1016/j.intimp.2015.05.019
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发表时间：
2015
影响因子：
5.6
通讯作者：
Qiyun
中科院分区：
文献类型：
--
作者：
Yang;Jianbin;Wang;Cheng;Nie;Xiaoke;Shi;Shangshi;Xiao;Jing;Ma;Xia;Dong;Xuan;Zhang;Yan;Han;Jingling;Li;Ting;Mao;Jiamin;Liu;Xinhang;Zhao;Jianya;Wu;Qiyun
全氟辛烷磺酸是一种普遍存在于环境和生物群中的污染物，可对人类健康造成多种不利影响。近年来，全氟辛烷磺酸对中枢神经系统的毒性作用已被证实。然而，PFOS神经毒性的潜在分子机制仍有许多研究工作要做。小胶质细胞是中枢神经系统的先天性免疫细胞，在由促炎介质引起的各种神经系统疾病中起着重要作用。本研究发现，PFOS暴露后HAPI小胶质细胞分泌肿瘤坏死因子-α（TNF-α），并呈时间和剂量依赖性。我们还发现PFOS处理后细胞内游离Ca 2+浓度（[Ca 2 +]i）显著增加。Ca 2+抑制剂和蛋白激酶C（PKC）抑制剂可阻断PFOS介导的TNF-α分泌。此外，PFOS还可上调磷酸化核因子κ B（NF-κ B）p65的表达，加速NF-κB抑制剂α（I κ Bα）的降解，但这些作用可被Ca 2+抑制剂和PKC抑制剂减弱或阻断。最后，我们用PFOS处理的小胶质细胞条件培养基处理SH-SY 5 Y细胞，证实TNF-α介导神经元凋亡。综上所述，我们的研究首次表明，PFOS在HAPI小胶质细胞中引起的TNF-α分泌是通过Ca 2+依赖的PKC-NF-кB信号传导实现的，随后参与了神经元的损失。
Perfluorooctane sulfonate (PFOS), a ubiquitous pollutant widely found in the environment and biota, can cause numerous adverse effects on human health. In recent years, PFOS's toxic effects on the central nervous system (CNS) have been shown. However, we still have a lot to study in the underlying molecular mechanism of PFOS's neurotoxicity. Microglia, the innate immune cells of CNS, are critically implicated in various neurological diseases caused by pro-inflammatory mediators. In our research, we found that HAPI microglia secreted tumor necrosis factor-alpha (TNF-α) after PFOS exposure in time-dependent and dose-dependent way. We also discovered that intracellular concentration of free Ca2 +([Ca2 +]i) significantly increased after PFOS treatments. It was noteworthy here the secretion of TNF-α mediated by PFOS was blocked by Ca2 +inhibitor and protein kinase C (PKC) inhibitor. Besides these, we had learned as well that PFOS brought about the up-regulation of phosphorylated nuclear factor kappa B (NF-кB) p65 expression and accelerated degradation of NF-κB inhibitor alpha (IкBα), however, these effects could be attenuated or blocked by Ca2 +inhibitor and PKC inhibitor. Finally, through treating SH-SY5Y cells with PFOS-treated microglial conditioned medium, we demonstrated that TNF-α mediated neuronal apoptosis. To sum up, our research had shown, for the first time, that the distinct TNF-α secretion brought by PFOS in HAPI microglia, was achieved through the Ca2 +-dependent PKC-NF-кB signaling, subsequently participating in neuronal loss.