Inhibition of HSP90β by ganetespib blocks the microglial signalling of evoked pro-inflammatory responses to heat shock
Inhibition of HSP90β by ganetespib blocks the microglial signalling of evoked pro-inflammatory responses to heat shock
复制标题
ganetespib 抑制 HSP90β 会阻断热休克引起的促炎症反应的小胶质细胞信号传导
DOI：
10.1016/j.biocel.2018.11.003
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Xue-Sen Yang
中科院分区：
文献类型：
--
作者：
Gen-Lin He;Zhen Luo;Ting-Ting Shen;Ju Yang;Ping Li;Xue Luo;Xue-Sen Yang
虽然小胶质细胞对热休克的反应被认为是保护性的，但热休克仍然是高温引起的潜在危害。最近的研究表明，抑制90 kDa热休克蛋白（HSP 90）增加保护性热休克反应和抑制炎症信号通路在几种疾病。然而，热休克对小胶质细胞促炎反应的影响并不完全相同。在这里，我们的目的是研究热休克后热休克蛋白90抑制剂ganetespib对小胶质细胞促炎反应的影响。通过用酶促制备的siRNA（esiRNA）转染N9小胶质细胞（N9细胞）来确定HSP 90同种型。我们发现热休克显著增加了肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1β、IL-6和一氧化氮（NO）的分泌，以及细胞外信号调节激酶（ERK）、Janus激活激酶2（JAK 2）、信号转导和转录激活因子3（STAT 3）的磷酸化，B细胞中κ轻链多肽基因增强子抑制剂α（IκB-α）和N9细胞中活化B细胞的p65核因子κ轻链增强子（p65 NF-κB）。除磷酸化p65外，这些增加通过ganetespib预处理以剂量依赖性方式有效减弱。此外，在热休克处理的N9细胞中，通过施用esiRNA HSP 90 β而不是HSP 90 α，还观察到热休克诱导的细胞因子和NO产生的抑制，以及细胞质和/或细胞核中ERK、JAK 2和STAT 3的磷酸化。总之，我们的研究结果表明，热休克90抑制剂ganetespib通过涉及HSP 90 β和STAT 3的信号传导机制阻断热休克处理的N9细胞中的促炎反应。
Although microglial reaction to heat shock is considered to be protective, heat shock is still a potential hazard caused by high temperatures. Recent studies indicate that the inhibition of the 90-kDa heat shock protein (HSP90) increasing the protective heat shock response and suppressing inflammatory signalling pathways in several diseases. Nevertheless, the effects of heat shock on microglial pro-inflammatory responses are not completely identical. Here, we aim to investigate the effect of the HSP90 inhibitor ganetespib on microglial pro-inflammatory responses following heat shock. HSP90 isoforms were determined by transfecting N9 microglial cells (N9 cells) with enzymatically prepared siRNA (esiRNAs). We found that heat shock significantly increased the secretion of tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6 and nitric oxide (NO), and the phosphorylation of extracellular signal–regulated kinase (ERK), Janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκB-α) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (p65 NF-κB) in N9 cells. These increases, except for phospho-p65, were attenuated efficiently in a dose-dependent manner by ganetespib pretreatment. Furthermore, the suppression of heat shock–evoked cytokines and NO production, and the phosphorylation of ERK, JAK2 and STAT3 in cytosols and/or nuclei were also observed by administering esiRNA HSP90β, but not HSP90α, in heat shock–treated N9 cells. Taken together, our findings demonstrate that the HSP90 inhibitor ganetespib blocks pro-inflammatory responses in heat shock–treated N9 cells via a signalling mechanism involving HSP90β and STAT3.