Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes.
Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes.
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DOI：
10.1186/1742-2094-9-52
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发表时间：
2012-03-15
影响因子：
9.3
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Shah A;Silverstein PS;Singh DP;Kumar A
甲基苯丙胺(MA)是一种常用的违禁药物，其中枢神经系统毒性是有据可查的。造成这种毒性的机制尚未完全阐明。在这项研究中，我们研究了MA对星形细胞系中促炎症细胞因子/趋化因子、IL-6和IL-8表达水平的影响。染毒3天后，IL-6和IL-8的RNA水平分别增加了4.6±0.2倍和3.5±0.2倍。星形胶质细胞暴露于MA 24小时后，IL-6和IL-8在RNA和蛋白质水平的表达均增加。核因子-κB(NF-KappaB)通路可能参与MA诱导IL-6和IL-8产生的可能机制(S)。SC514可显著抑制MA诱导的IL-6和IL-8的升高。我们还发现，星形胶质细胞暴露于MA后，通过IκB-κ的磷酸化导致NF-αB的激活，然后将活性的NF-κB从细胞质转移到细胞核。此外，用代谢型谷氨酸受体-5(MGluR5)的特异性抑制剂处理细胞，发现MA介导的IL-6和IL-8的表达水平分别被抑制了42.6±5.8%和65.5±3.5%。Akt/PI3K通路的抑制剂LY294002使MA诱导的IL-6和IL-8分别减少了77.9±6.6%和81.4±2.6%。因此，我们的研究证明了核因子-κB介导的信号机制参与了MA诱导IL-6和IL-8的过程。此外，我们发现阻断mGluR5可以保护星形胶质细胞免受MA介导的促炎细胞因子/趋化因子的增加，这表明mGluR5可能是治疗MA介导的神经毒性的潜在治疗靶点。
Methamphetamine (MA) is one of the commonly used illicit drugs and the central nervous system toxicity of MA is well documented. The mechanisms contributing to this toxicity have not been fully elucidated. In this study, we investigated the effect of MA on the expression levels of the proinflammatory cytokines/chemokines, IL-6 and IL-8 in an astrocytic cell line. The IL-6 and IL-8 RNA levels were found to increase by 4.6 ± 0.2 fold and 3.5 ± 0.2 fold, respectively, after exposure to MA for three days. Exposure of astrocytes to MA for 24 hours also caused increased expression of IL-6 and IL-8 at the level of both RNA and protein. The potential involvement of the nuclear factor-Kappa B (NF-κB) pathway was explored as one of the possible mechanism(s) responsible for the increased induction of IL-6 and IL-8 by MA. The MA-mediated increases in IL-6 and IL-8 were significantly abrogated by SC514. We also found that exposure of astrocytes to MA results in activation of NF-κB through the phosphorylation of IκB-α, followed by translocation of active NF-κB from the cytoplasm to the nucleus. In addition, treatment of cells with a specific inhibitor of metabotropic glutamate receptor-5 (mGluR5) revealed that MA-mediated expression levels of IL-6 and IL-8 were abrogated by this treatment by 42.6 ± 5.8% and 65.5 ± 3.5%, respectively. Also, LY294002, an inhibitor of the Akt/PI3K pathway, abrogated the MA-mediated induction of IL-6 and IL-8 by 77.9 ± 6.6% and 81.4 ± 2.6%, respectively. Thus, our study demonstrates the involvement of an NF-κB-mediated signaling mechanism in the induction of IL-6 and IL-8 by MA. Furthermore, we showed that blockade of mGluR5 can protect astrocytes from MA-mediated increases of proinflammatory cytokines/chemokines suggesting mGluR5 as a potential therapeutic target in treating MA-mediated neurotoxicity.
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影响因子：
2.3
作者：
Bowyer, John F.;Ali, Syed
通讯作者：
Ali, Syed
DOI：
10.1111/j.1749-6632.1998.tb08224.x
发表时间：
1998-01-01
期刊：
NEUROCHEMISTRY OF DRUGS OF ABUSE
影响因子：
--
作者：
Jayanthi, S;Ladenheim, B;Cadet, JL
通讯作者：
Cadet, JL
影响因子：
3.4
作者：
Goncalves, Joana;Baptista, Sofia;Silva, Ana P.
通讯作者：
Silva, Ana P.
影响因子：
3.9
作者：
Morgan, JE
通讯作者：
Morgan, JE
影响因子：
4.7
作者：
Guillot TS;Shepherd KR;Richardson JR;Wang MZ;Li Y;Emson PC;Miller GW
通讯作者：
Miller GW