Crosstalk between JNK and NF-κB in the KDO2-mediated production of TNFα in HAPI cells.
Crosstalk between JNK and NF-κB in the KDO2-mediated production of TNFα in HAPI cells.
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HAPI 细胞中 KDO2 介导的 TNFα 生产中 JNK 和 NF-κB 之间的串扰。
DOI：
10.1007/s10571-012-9864-9
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发表时间：
2012
影响因子：
4
通讯作者：
Hao,Shuanglin
中科院分区：
文献类型：
--
作者：
Zheng,Xuexing;Zheng,Wenwen;Liu,Shue;Patel,HarshilM;Xia,Xianzhu;Ouyang,Hongsheng;Levitt,RoyC;Candiotti,KeithA;Hao,Shuanglin
核因子κ B（NF-κB）和丝裂原活化蛋白激酶均介导许多类型细胞中促炎细胞因子的产生。c-Jun N-末端激酶（JNK）是许多细胞事件（包括细胞炎症和/或程序性细胞死亡（凋亡））的关键调节剂。除了介导免疫和炎症反应外，NF-κB转录因子还控制细胞存活。据报道，NF-κB的活化通过多种触发剂拮抗细胞凋亡或程序性细胞死亡。已有报道，在肿瘤坏死因子α（TNFα）处理的小鼠胚胎成纤维细胞中，NF-κB活化导致JNK快速失活。JNK与NF-κB B在TLR 4活性诱导的小胶质细胞中的关系尚不清楚。在本研究中，我们研究了JNK和NF-κB在高度增殖的永生化小胶质细胞系中的关系。KDO 2处理可显著诱导JNK和NF-κB的磷酸化，并释放TNFα。用TLR 4 siRNA敲低TLR 4显著降低JNK（pJNK）磷酸化、NF-κB磷酸化和TNFα释放。抑制JNK可减少TNFα的释放，但不能减少NF-κB的磷酸化。出乎意料的是，NF-κB的抑制增强了pJNK和TNFα的释放。这些结果表明KDO 2诱导的TNFα是JNK依赖性的，NF-κB B负性调节pJNK和TNFα。本研究可能为小胶质细胞系中TNFα的调节提供新的见解。
Both nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases mediate production of proinflammatory cytokines in many types of cells. c-Jun N-terminal kinases (JNK) is a key regulator of many cellular events including cell inflammation and/or programmed cell death (apoptosis). In addition to mediating immune and inflammatory responses, NF-κB transcription factors control cell survival. It is reported that activation of NF-κB antagonizes apoptosis or programmed cell death by numerous triggers. It has been reported that NF-κB activation results in rapid inactivation of JNK in tumor necrosis factor alpha (TNFα)-treated murine embryonic fibroblasts. It is not clear about the relationship of JNK and NF-κB in the microglial cells induced by TLR4 activity. In the present study, we investigated the relationship of JNK and NF-κB in the highly aggressively proliferating immortalized microglial cell line treated with KDO2 (a TLR4 agonist). KDO2 treatment significantly induced the phosphorylation of JNK and NF-κB, and released TNFα. Knockdown of TLR4 with TLR4 siRNA significantly reduced phosphorylation of JNK (pJNK), phosphorylation of NF-κB, and release of TNFα. Inhibition of JNK reduced the release of TNFα, but not phosphorylation of NF-κB. Unexpectedly, inhibition of NF-κB enhanced pJNK and the release of TNFα. These results showed that TNFα induced by KDO2 was JNK-dependent, and that NF-κB negatively modulated both pJNK and TNFα in the cultured microglial cell line. The current study may provide a new insight in the modulation of TNFα in the microglial cell line.