15-脱氧-Δ12,14-前列腺素 J₂ 调节锰诱导的星形胶质细胞中 NF-κB、Nrf2 和 PI3K 通路的激活。
15-Deoxy-Δ12,14-prostaglandin J₂ modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes.
机构信息
Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA.
出版信息
Free Radic Biol Med. 2012 Mar 15;52(6):1067-74. doi: 10.1016/j.freeradbiomed.2011.12.016. Epub 2011 Dec 29.
Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E(2). Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J(2) (15 d-PGJ(2)) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ(2) modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ(2) suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ(2) (10 μM for 1h) significantly (p<0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p<0.05) decreased NF-κB activation. 15 d-PGJ(2) also significantly (p<0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ(2) to modulate the Nrf2 pathway. 15 d-PGJ(2) significantly (p<0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ(2) partially suppressed (p<0.01) the 15 d-PGJ(2)-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p<0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ(2) attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15d-PGJ(2) exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.
过量的锰（Mn）暴露会增加氧化应激因子和促炎介质的水平，如环氧化酶-2 和前列腺素 E（2）。Mn 还会激活核因子-κB（NF-κB），这是炎症的一个重要介质。信号分子 15-脱氧-Δ12,14-前列腺素 J（15d-PGJ）是一种抗炎性前列腺素。在这里，我们测试了 15d-PGJ 调节 Mn 诱导的星形胶质细胞细胞内信号转导的假设，包括 NF-κB 和核因子红细胞 2 相关因子（Nrf2），这是抗氧化转录反应的主要调节剂。结果表明，15d-PGJ 通过与多个信号通路相互作用来抑制 Mn 诱导的 NF-κB 激活。PI3K/Akt 通路是 NF-κB 的上游通路，在这种激活中起作用，因为（i）用 15d-PGJ（10μM 预处理 1h）显著（p<0.01）抑制了 Mn（500μM）诱导的 PI3K/Akt 激活，（ii）用 LY29004 抑制 PI3K/Akt 通路显著（p<0.05）降低了 NF-κB 的激活。15d-PGJ 还通过抑制 Mn 诱导的 IκB 激酶磷酸化和随后的 IκB-α 降解，显著（p<0.05）减弱了 Mn 诱导的星形胶质细胞 NF-κB 激活。由于 Mn 诱导的氧化应激也与 Nrf2 激活有关，因此进行了进一步的研究来确定 15d-PGJ 调节 Nrf2 通路的能力。15d-PGJ 显著（p<0.01）增加了全细胞裂解物中的 Nrf2 表达。与它的促氧化剂特性一致，Mn 也增加了 Nrf2 的表达。然而，Mn 和 15d-PGJ 共同处理全细胞裂解物部分抑制（p<0.01）了 15d-PGJ 诱导的星形胶质细胞 Nrf2 蛋白表达的增加。Mn 处理还降低了（p<0.001）帕金森病相关蛋白 DJ-1 的表达，DJ-1 是 Nrf2 的稳定剂，而 15d-PGJ 减弱了 Mn 诱导的星形胶质细胞 DJ-1 表达抑制。总之，这些结果表明，15d-PGJ 通过调节 NF-κB 和 Nrf2 信号通路的激活，在星形胶质细胞中对 Mn 诱导的炎症和氧化应激发挥保护作用。
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