Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death
Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death
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DOI：
10.1111/j.1471-4159.2006.04330.x
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Combs, Colin K.
中科院分区：
文献类型：
--
作者：
Jara, Javier H.;Singh, Brij B.;Combs, Colin K.
在促炎条件下，多种细胞因子在大脑中分泌，并可能影响神经元的存活。之前，我们证明了谷氨酸和肿瘤坏死因子α (TNF α)分别通过激活n -甲基- d -天冬氨酸（NMDA）和TNF α受体来杀死神经元。本报告继续描述炎症相关死亡机制中启动的信号串扰通路。用TNF α刺激小鼠皮层神经元培养可导致NMDA受体依赖性钙内流的短暂性增加，这种增加与NMDA刺激同时发生，并可通过NMDA受体拮抗剂dl -2-氨基-5-磷酸戊酸或α -氨基-3-羟基-5-甲基异恶唑-4-丙酸盐/海因酸受体拮抗剂6,7-二硝基喹啉-2,3-二酮预处理来抑制。用n型钙通道拮抗剂（ω - concontoxin）或电压门控钠通道拮抗剂（河豚毒素）进行预处理，也可防止TNF α刺激的钙内流。联合TNF α和NMDA刺激导致细胞外信号调节激酶（ERKs）和c-Jun n -末端激酶（JNKs）活性的短暂增加。特异性抑制ERKs而非JNKs对TNF α和nmda依赖性死亡具有保护作用。死亡是通过低亲和力TNF α受体TNFRII作为TNFRII的激动剂抗体介导的，但TNFRI不会刺激NMDA受体依赖性钙内流和死亡。这些数据证明了包括TNF α在内的小胶质促炎分泌物如何急性促进谷氨酸依赖的神经元死亡。
Multiple cytokines are secreted in the brain during pro-inflammatory conditions and likely affect neuron survival. Previously, we demonstrated that glutamate and tumor necrosis factor alpha (TNF alpha) kill neurons via activation of the N-methyl-D-aspartate (NMDA) and TNF alpha receptors, respectively. This report continues characterizing the signaling cross-talk pathway initiated during this inflammation-related mechanism of death. Stimulation of mouse cortical neuron cultures with TNF alpha results in a transient increase in NMDA receptor-dependent calcium influx that is additive with NMDA stimulation and inhibited by pre-treatment with the NMDA receptor antagonist, DL-2-amino-5-phosphonovaleric acid, or the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. Pre-treatment with N-type calcium channel antagonist, omega-conotoxin, or the voltage-gated sodium channel antagonist, tetrodotoxin, also prevents the TNF alpha-stimulated calcium influx. Combined TNF alpha and NMDA stimulation results in a transient increase in activity of extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Specific inhibition of ERKs but not JNKs is protective against TNF alpha and NMDA-dependent death. Death is mediated via the low-affinity TNF alpha receptor, TNFRII, as agonist antibodies for TNFRII but not TNFRI stimulate NMDA receptor-dependent calcium influx and death. These data demonstrate how microglial pro-inflammatory secretions including TNF alpha can acutely facilitate glutamate-dependent neuron death.