Si Qiusheng, Cosenza Melissa, Zhao Meng-Liang, Goldstein Harris, Lee Sunhee C
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Glia. 2002 Aug;39(2):174-83. doi: 10.1002/glia.10095.
Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.
大量获得性免疫缺陷综合征（AIDS）患者主要在巨噬细胞和小胶质细胞中发生中枢神经系统感染。因此，人类免疫缺陷病毒1型（HIV-1）感染的调控以及感染后脑单核吞噬细胞的激活是重要的研究领域。在本报告中，我们研究了粒细胞-巨噬细胞集落刺激因子（GM-CSF）和巨噬细胞集落刺激因子（M-CSF）在原代人胎儿小胶质细胞培养物中抗病毒β-趋化因子表达和HIV-1 p24表达中的作用。我们发现，在小胶质细胞感染HIV-1后，用GM-CSF或M-CSF刺激可诱导巨噬细胞炎性蛋白（MIP-1α和MIP-1β）并增强RANTES表达。这并非由于GM-CSF对病毒表达的影响，因为GM-CSF对病毒感染既非必需也无刺激作用，GM-CSF也未增强env假型报告病毒的表达。用诺考达唑阻断GM-CSF诱导的小胶质细胞增殖对β-趋化因子或p24表达无影响。GM-CSF诱导的β-趋化因子的功能意义体现在以下发现中：在GM-CSF存在的情况下，外源性β-趋化因子失去了其抗HIV-1的作用。我们进一步表明，虽然HIV-1感染的小胶质细胞产生M-CSF，但它们未能产生GM-CSF。在体内，GM-CSF表达定位于HIV-1脑炎中活化的星形胶质细胞和一些炎性细胞，提示通过GM-CSF对小胶质细胞进行旁分泌激活。我们的结果证明了小胶质细胞中集落刺激因子、趋化因子和病毒之间存在复杂的相互作用，这可能对体内和体外数据的解释有影响。
