Kappa-opioid potentiation of tumor necrosis factor-alpha-induced anti-HIV-1 activity in acutely infected human brain cell cultures.
Kappa-opioid potentiation of tumor necrosis factor-alpha-induced anti-HIV-1 activity in acutely infected human brain cell cultures.
复制标题
在急性感染的人脑细胞培养物中，κ-阿片类药物增强肿瘤坏死因子-α诱导的抗 HIV-1 活性。
DOI：
10.1016/s0006-2952(98)00161-0
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发表时间：
1998
影响因子：
5.8
通讯作者：
Peterson,PK
中科院分区：
文献类型：
--
作者：
Chao,CC;Gekker,G;Hu,S;Kravitz,F;Peterson,PK
阿片类药物被认为在HIV-1的发病机制中发挥免疫调节作用。已发现合成的κ-阿片受体（KOR）配体抑制急性感染的小胶质细胞培养物中的HIV-1表达。我们最近发现，白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α在急性感染的神经胶质/神经元混合细胞培养中具有抗病毒作用。在本研究中，我们研究了选择性KOR配体是否会在急性感染的脑细胞培养中发挥抗病毒作用。虽然KOR配体反式-3，4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]苯乙酰胺甲磺酸盐（U 50，488）单独具有很小的抗HIV-1活性，但这种阿片类药物以浓度依赖性方式增强TNF-α的抗病毒活性，但不增强IL-1β的抗病毒活性。U 50，488预处理6小时后可检测到增强作用，并在24小时达到峰值，KOR拮抗剂nor-binaltorphimine可完全阻断U 50，488的增强作用，提示其参与KOR介导的机制。TNF-α抗体完全阻断了U 50，488的增强作用，表明TNF-α的关键作用。抗IL-1β抗体阻断了U 50，488的增强作用，表明IL-1β在U 50，488处理后释放，这可能有助于U 50，488的增强作用。这些体外研究结果支持了这样的观点，即合成的κ-阿片类药物可被视为HIV-1相关脑疾病的潜在治疗药物。
Opioids have been postulated to play an immunomodulatory role in the pathogenesis of HIV-1. Synthetic κ-opioid receptor (KOR) ligands have been found to inhibit HIV-1 expression in acutely infected microglial cell cultures. We recently found that interleukin(IL)-1β and tumor necrosis factor(TNF)-α have antiviral effects in acutely infected mixed glial/neuronal cell cultures. In the present study, we investigated whether selective KOR ligands would exert antiviral effects in acutely infected brain cell cultures. While the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) alone had little anti-HIV-1 activity, this opioid potentiated in a concentration-dependent manner the antiviral activity of TNF-α, but not of IL-1β. The potentiating effect of U50,488 was detected after a 6-hr pretreatment and peaked at 24 hr. The KOR antagonist nor-binaltorphimine completely blocked the potentiating effect of U50,488, suggesting the involvement of a KOR-mediated mechanism. Antibodies to TNF-α completely blocked the potentiating effect of U50,488, suggesting a critical role for TNF-α. Antibodies to IL-1β blocked the potentiating effect of U50,488, suggesting that IL-1β was released following U50,488 treatment, which might contribute to the potentiating effect of U50,488. These in vitro findings support the notion that synthetic κ-opioids could be considered as potential adjunctive therapeutic agents in HIV-1-related brain disease.