Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
J Pharmacol Sci. 2022 May;149(1):1-10. doi: 10.1016/j.jphs.2022.02.004. Epub 2022 Feb 20.
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.
一些化学 Nrf2 诱导剂具有抗氧化和抗炎特性。TPNA10168 是从化学文库中鉴定出的一种潜在的 Keap1-Nrf2-ARE 通路激活剂，具有对抗氧化应激诱导损伤的神经保护作用。然而，它尚未被研究作为一种抗炎剂。在这里，我们研究了 TPNA10168 对小鼠小胶质细胞 BV-2 细胞中干扰素-γ诱导的促炎基因表达的影响。TPNA10168 显著降低了 TNF-α、IL-1β、IL-6 和 iNOS 等炎症基因的转录；然而，Nrf2 调节酶抑制剂并不能减弱促炎细胞因子基因表达的抑制作用。此外，TPNA10168 甚至在 Nrf2 缺陷细胞中也表现出抗炎作用，并抑制干扰素-γ诱导的细胞外信号调节激酶 (ERK) 磷酸化。ERK 通路抑制剂的研究表明，ERK 在炎症基因的转录中起作用。这些结果表明，TPNA10168 可减轻小胶质细胞的促炎激活，至少部分通过抑制干扰素-γ诱导的 ERK 信号转导，与 Nrf2 无关。
