Sanders V J, Everall I P, Johnson R W, Masliah E
Department of Neurosciences, University of California, San Diego, La Jolla 92093-0624, USA.
J Neurosci Res. 2000 Mar 1;59(5):671-9. doi: 10.1002/(SICI)1097-4547(20000301)59:5<671::AID-JNR10>3.0.CO;2-B.
Recent studies suggest that the chemokine receptor CXCR4 may be involved in mediating the neurodegenerative process in the brains of patients with acquired immunodeficiency disease (AIDS). In this context, we hypothesize that neurotrophic factors, such as fibroblast growth factor (FGF), might protect against human immunodeficiency virus (HIV)-mediated neurotoxicity via regulating the expression of CXCR4 in neural cells. For this purpose, levels of CXCR4 were determined in neuronal and glial cell lines after FGF1 and 2 treatment. In addition, levels of CXCR4 immunoreactivity were associated with levels of FGF1 immunoreactivity in the brains of HIV-positive patients. These studies showed that neuronal CXCR4 levels decreased in a dose-dependent manner after exposure to FGF. Conversely, glial CXCR4 was increased in a dose-dependent manner after FGF2 treatment. These effects were dependent on the FGF receptor tyrosine kinase signaling pathway, because FGF-induced effects on CXCR4 were blocked by the tyrosine kinase inhibitor, 5'-deoxy-5'methylthioadenosine, or by anti-FGF receptor antibody. Stromal cell-derived factor-1, the ligand for CXCR4, and HIV gp120 neurotoxicity was attenuated by FGF1 in a dose-dependent manner in vitro, further supporting physiological relevance. In the brains of AIDS patients, the levels of neural CXCR4 immunoreactivity were inversely associated with FGF levels. Taken together, these results support the possibility that the neuroactive effects of FGF in HIV encephalitis might be mediated through regulation of the expression of CXCR4.
近期研究表明，趋化因子受体CXCR4可能参与介导获得性免疫缺陷病（AIDS）患者大脑中的神经退行性过程。在此背景下，我们推测神经营养因子，如成纤维细胞生长因子（FGF），可能通过调节神经细胞中CXCR4的表达来抵御人类免疫缺陷病毒（HIV）介导的神经毒性。为此，在FGF1和FGF2处理后，测定了神经元和神经胶质细胞系中CXCR4的水平。此外，在HIV阳性患者的大脑中，CXCR4免疫反应性水平与FGF1免疫反应性水平相关。这些研究表明，暴露于FGF后，神经元CXCR4水平呈剂量依赖性下降。相反，FGF2处理后，神经胶质细胞CXCR4呈剂量依赖性增加。这些效应依赖于FGF受体酪氨酸激酶信号通路，因为酪氨酸激酶抑制剂5'-脱氧-5'-甲硫腺苷或抗FGF受体抗体可阻断FGF对CXCR4的诱导效应。CXCR4的配体基质细胞衍生因子-1和HIV gp120神经毒性在体外被FGF1以剂量依赖性方式减弱，进一步支持了其生理相关性。在AIDS患者的大脑中，神经CXCR4免疫反应性水平与FGF水平呈负相关。综上所述，这些结果支持FGF在HIV脑炎中的神经活性作用可能通过调节CXCR4的表达来介导的可能性。
