MDMA ("Ecstasy") suppresses the innate IFN-γ response in vivo:: A critical role for the anti-inflammatory cytokine IL-10
MDMA ("Ecstasy") suppresses the innate IFN-γ response in vivo:: A critical role for the anti-inflammatory cytokine IL-10
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DOI：
10.1016/j.ejphar.2007.07.020
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发表时间：
2007-10-31
影响因子：
5
通讯作者：
Connor, Thomas J.
中科院分区：
文献类型：
--
作者：
Boyle, Noreen T.;Connor, Thomas J.
在这里，我们证明了广泛滥用的药物亚甲二氧基甲基苯丙胺（MDMA;“摇头丸”）抑制先天性干扰素（IFN）-γ的产生在小鼠体内脂多糖（LPS）的挑战。IFN-γ信号传导也受到MDMA的损害，表现为信号转导和转录激活因子-1（STAT 1）磷酸化水平降低以及IFN-γ诱导蛋白10（IP-10/CXCL 10）（IFN-γ诱导的一种趋化因子）表达降低。MDMA还抑制白细胞介素（IL）-12和IL-15的产生;这两种细胞因子诱导IFN-γ的产生。我们的研究结果表明，在体外暴露于MDMA不模仿抑制先天性IFN-γ在体内观察到，表明观察到的抑制是最有可能由于内源性免疫调节物质的释放后，药物管理。在这方面，我们之前证明了MDMA会增加体内抗炎细胞因子IL-10的产生，这是由免疫细胞上的β肾上腺素受体激活介导的事件。考虑到IL-10产生增加先于MDMA诱导的IFN-γ抑制。并且考虑到IL-10可以抑制IL-12和IFN-γ的产生，我们检测了IL-10是MDMA对IFN-γ应答的抑制作用的重要介质的可能性。通过用抗IL-10受体抗体预处理小鼠，我们证明IL-10是MDMA诱导的IFN-γ产生和信号传导抑制的关键介质。与β-肾上腺素受体激活在MDMA免疫抑制作用中的作用一致，用β-肾上腺素受体拮抗剂纳多洛尔预处理阻断了MDMA诱导的IL-10增加，也抑制了MDMA对先天IFN-γ反应的抑制作用。潜在的临床意义，这些研究结果MDMA用户进行了讨论。(c)2007 Elsevier B. V.保留所有权利。
Here we demonstrate that the widely abused drug methylenedioxymethamphetamine (MDMA; "Ecstasy") suppresses innate interferon (IFN)-gamma production in mice following an in vivo lipopolysaccharide (LPS) challenge. IFN-gamma signalling was also impaired by MDMA, as indicated by reduced phosphorylation of signal transducer and activator of transcription-1 (STAT1) and reduced expression of interferon-gamma inducible protein 10 (IP-10/CXCL10); a chemokine induced by IFN-gamma. MDMA also suppressed production of interleukin (IL)-12 and IL-15; two cytokines that induce IFN-gamma production. Our results demonstrate that in vitro exposure to MDMA does not mimic the suppression of innate IFN-gamma observed in vivo, indicating that observed suppression is most likely due to the release of endogenous immunomodulatory substances following drug administration. In this regard, we previously demonstrated that MDMA increases production of the anti-inflammatory cytokine IL-10 in vivo, an event that is mediated by beta-adrenoceptor activation on immune cells. Considering that increased IL-10 production precedes suppression of IFN-gamma induced by MDMA. and also considering that IL-10 can inhibit IL-12 and IFN-gamma production, we examined the possibility that IL-10 was an essential mediator of the suppressive effect of MDMA on the IFN-gamma response. By pre-treating mice with an anti-IL-10 receptor antibody we demonstrate that IL-10 is a critical mediator of MDMA-induced suppression of IFN-gamma production and signalling. Consistent with a role for beta-adrenoceptor activation in the immunosuppressive actions of MDMA, pre-treatment with the beta-adrenoceptor antagonist nadolol blocked the MDMA-induced increase in IL-10, and also inhibited the suppressive action of MDMA on the innate IFN-gamma response. The potential clinical significance of these findings for MDMA users is discussed. (c) 2007 Elsevier B.V. All rights reserved.