TPNA10168, an Nrf-2 activator, attenuates inflammatory responses independently of Nrf2 in microglial BV-2 cells: Involvement of the extracellular-signal-regulated kinase pathway.
TPNA10168, an Nrf-2 activator, attenuates inflammatory responses independently of Nrf2 in microglial BV-2 cells: Involvement of the extracellular-signal-regulated kinase pathway.
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TPNA10168 是一种 Nrf-2 激活剂，可独立于小胶质细胞 BV-2 细胞中的 Nrf2 减弱炎症反应：参与细胞外信号调节激酶途径。
DOI：
10.1016/j.jphs.2022.02.004
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Koyama Y.
中科院分区：
文献类型：
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作者：
Izumi Y;Tatsumoto A;Horiuchi N;Arifuku M;Uegomori M;Kume T;Koyama Y.
一些化学NRF2诱导剂具有抗氧化和抗炎特性。TPNA10168被从化学文库中鉴定为Keap1-Nrf2-ARE途径的潜在激活剂，对氧化应激诱导的损伤具有神经保护作用。然而，它还没有被作为抗炎剂进行研究。在这里，我们检测了TPNA10168对干扰素-γ诱导的小鼠小胶质细胞BV-2细胞促炎基因表达的影响。TPNA10168显著降低炎症基因的转录，包括肿瘤坏死因子α、白介素1β、白介素6和诱导型一氧化氮合酶，而促炎细胞因子基因表达的抑制不能被NRF2调节的酶的抑制剂所减弱。此外，TPNA10168具有抗炎作用，即使在NRF2缺失的细胞中也是如此，并抑制干扰素γ诱导的细胞外信号调节激酶的磷酸化。对ERK途径抑制剂的研究表明，ERK在炎症基因的转录中发挥作用。这些结果表明，TPNA10168至少部分地通过抑制干扰素-γ诱导的ERK信号通路来减轻不依赖于NRF2的小胶质细胞前炎症激活。
Some chemical Nrf2 inducers possess antioxidant and anti-inflammatory properties. TPNA10168, which was identified from a chemical library as a potential activator of the Keap1-Nrf2-ARE pathway, exhibits a neuroprotective effect against oxidative stress-induced injury. However, it has not been investigated as an anti-inflammatory agent. Here we examined the effect of TPNA10168 on interferon-γ-induced proinflammatory gene expression in mouse microglial BV-2 cells. TPNA10168 significantly reduced the transcription of inflammatory genes, including TNF-α, IL-1β, IL-6, and iNOS; however, the inhibition of proinflammatory cytokine gene expression was not attenuated by inhibitors of Nrf2-regulated enzymes. Furthermore, TPNA10168 showed anti-inflammatory effects, even in Nrf2-deficient cells, and inhibited interferon-γ-induced phosphorylation of extracellular-signal-regulated kinase (ERK). Studies with an ERK pathway inhibitor demonstrated a role for ERK in the transcription of inflammatory genes. These results suggest that TPNA10168 attenuates microglial proinflammatory activation independently of Nrf2, at least in part, by suppressing interferon-γ-induced ERK signaling.