Mahajan Supriya D, Schwartz Stanley A, Shanahan Thomas C, Chawda Ram P, Nair Madhavan P N
Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, Kaleida Health System, Buffalo, NY 14203, USA.
J Immunol. 2002 Oct 1;169(7):3589-99. doi: 10.4049/jimmunol.169.7.3589.
The brain is a target organ for recreational drugs and HIV-1. Epidemiological data demonstrate that opioid abuse is a risk factor for HIV-1 infection and progression to AIDS. Chemokines and their receptors have been implicated in the neuropathogenesis of HIV-1 infections. However, little is known about the effects of opioids on the expression of chemokines and their receptors (the latter also are HIV-1 coreceptors) by cells of the CNS. Herein we describe the effects of morphine on gene expression of the alpha- and beta-chemokines and their receptors by the astrocytoma cell line U87 and by primary normal human astrocyte (NHA) cultures. U87 cells treated with morphine showed significant down-regulation of IL-8 gene expression, whereas expression of the IL-8 receptor CXCR2 was reciprocally up-regulated as detected by RT-PCR. Treatment of NHAs with morphine suppressed IL-8 and macrophage-inflammatory protein-1beta gene expression, whereas expression of their receptor genes, CCR3 and CCR5, was simultaneously enhanced. These morphine-induced effects on U87 and NHA cells were reversed by the opioid mu receptor antagonist beta-funaltrexamine. Morphine also enhanced the constitutive expression of the opioid mu receptor on astroglial cells. Our results support the hypothesis that opioids play a significant role in the susceptibility of the CNS to HIV-1 infection and subsequent encephalopathy by inhibiting local production of HIV-1-protective chemokines (IL-8 and macrophage-inflammatory protein-1beta) and enhancing expression of HIV-1 entry coreceptor genes (CCR3, CCR5, and CXCR2) within the CNS. These effects of opioids appear to be mediated through the opioid mu receptor that we demonstrated on astroglial cells.
大脑是娱乐性药物和HIV-1的靶器官。流行病学数据表明，阿片类药物滥用是HIV-1感染及发展为艾滋病的一个危险因素。趋化因子及其受体与HIV-1感染的神经发病机制有关。然而，关于阿片类药物对中枢神经系统细胞趋化因子及其受体（后者也是HIV-1共受体）表达的影响却知之甚少。在此，我们描述了吗啡对星形细胞瘤细胞系U87和原代正常人星形胶质细胞（NHA）培养物中α-和β-趋化因子及其受体基因表达的影响。用吗啡处理的U87细胞显示IL-8基因表达显著下调，而通过逆转录聚合酶链反应检测到IL-8受体CXCR2的表达则相应上调。用吗啡处理NHA可抑制IL-8和巨噬细胞炎性蛋白-1β基因表达，而其受体基因CCR3和CCR5的表达则同时增强。阿片类μ受体拮抗剂β-氟纳曲胺可逆转吗啡对U87和NHA细胞的这些作用。吗啡还增强了星形胶质细胞上阿片类μ受体的组成性表达。我们的结果支持这样一种假说，即阿片类药物通过抑制HIV-1保护性趋化因子（IL-8和巨噬细胞炎性蛋白-1β）的局部产生以及增强中枢神经系统内HIV-1进入共受体基因（CCR3、CCR5和CXCR2）的表达，在中枢神经系统对HIV-1感染及随后的脑病易感性中起重要作用。阿片类药物的这些作用似乎是通过我们在星形胶质细胞上证实的阿片类μ受体介导的。
