The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice.
The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice.
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DOI：
10.1016/j.ejphar.2015.05.040
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发表时间：
2015-09-05
影响因子：
5
通讯作者：
Stevens CW
中科院分区：
文献类型：
--
作者：
Davis RL;Das S;Thomas Curtis J;Stevens CW
当阿片类药物改变免疫系统的活性时，就会发生阿片类免疫串扰。在这项研究中，阿片拮抗剂β-富纳曲胺（β-FNA）可降低白细胞介素1β (IL-1β)刺激的正常人类星形胶质细胞中炎症趋化因子干扰素γ诱导蛋白-10 （CXCL10）的表达和释放。β-FNA通过不涉及mu阿片受体（MOR）的未知作用降低CXCL10。由于IL-1β通过其受体激活NF-κB/MAPK信号通路，导致CXCL10的表达和释放，IL-1β信号通路的关键步骤在β-FNA处理后被检测。il -1β诱导的p38丝裂原活化蛋白激酶（p38 MAPK）的活化被β-FNA抑制，这表明在处理的细胞中p38 MAPK磷酸化降低。β-FNA还降低了处理后星形胶质细胞中NF-κB活化亚基（p50和p65）的水平。在负调节NF-κB信号传导的蛋白中也观察到β-FNA的影响。IL-1β可上调A20的表达，A20是一种泛素（Ub）编辑酶，通过改变IL-1受体第二信使的泛素化模式来抑制NF-κB信号传导，而β-FNA可显著抑制A20的表达。抑制剂PYR41对ub活化酶E1的抑制也像β-FNA一样降低了CXCL10的释放，并且PYR41和β-FNA同时治疗比单独使用任何一种药物更能抑制CXCL10。在小鼠脑中，脂多糖诱导的CXCL10表达被β-FNA抑制。这些结果表明，β-FNA在体外和体内均具有与摩尔无关的抗炎作用，可能与β-FNA的烷基化能力有关。
Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist β-funaltrexamine (β-FNA) decreases the expression and release of an inflammatory chemokine, interferon-γ inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1β (IL-1β). β-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1β acts through its receptor to activate NF-κB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1β signaling pathways were examined following β-FNA treatment. IL-1β-induced activation of p38 mitogen-activated protein kinases (p38 MAPK) was inhibited by β-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. β-FNA also decreased the levels of activated subunits of NF-κB (p50 and p65) in treated astrocytes. The impact of β-FNA was also observed in proteins that act to negatively regulate NF-κB signaling. IL-1β upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-κB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by β-FNA treatment. Inhibition of the Ub-activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like β-FNA, and concurrent treatment with both PYR41 and β-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with β-FNA. These findings suggest that β-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of β-FNA.