Lokensgard J R, Gekker G, Ehrlich L C, Hu S, Chao C C, Peterson P K
Minneapolis Medical Research Foundation, University of Minnesota Medical School 55404, USA.
J Immunol. 1997 Mar 1;158(5):2449-55.
An understanding of how viral replication in glial cells responds to proinflammatory cytokines is important in delineating HIV-1 neuropathogenesis. Because no information is available in the literature regarding the regulatory effects of exogenous cytokines on acute HIV-1 replication in human brain cells, we studied the impact of cytokine treatment on viral p24 Ag expression. Based upon reports using mononuclear phagocytes derived from somatic sources, we hypothesized that TNF-alpha, IL-1 beta, and IL-6 would up-regulate the expression of HIV-1(SF162) (a monocytotropic strain) in purified microglial cells and in mixed brain cell cultures. This hypothesis was not supported. In fact, a contrary, unexpected result was obtained; whereas in purified microglial cultures TNF-alpha displayed a mild stimulatory effect on HIV-1 expression (15% increase in p24 Ag production compared with control cultures), surprisingly, IL-1 beta and IL-6 were highly suppressive (91 and 83% inhibition of HIV expression, respectively). In contrast to the findings in microglial cell cultures, TNF-alpha profoundly suppressed (84%) HIV-1 expression in mixed brain cell cultures, as did IL-1 beta (82%), and IL-6 was moderately suppressive (55% inhibition). In an attempt to identify factors responsible for the differential effects of TNF-alpha in the two brain cell infection models, it was found that compared with microglial cell cultures, TNF-alpha treatment of mixed brain cell cultures released significantly greater amounts of RANTES (regulated upon activation, normal T cell expressed and secreted) and macrophage inflammatory protein-1 alpha, beta-chemokines that have been suggested to have anti-HIV-1 effects. Thus, these data suggest that proinflammatory cytokines possess anti-HIV-1 activity in the central nervous system.
了解神经胶质细胞中的病毒复制如何响应促炎细胞因子对于阐明HIV-1神经发病机制至关重要。由于文献中没有关于外源性细胞因子对人脑细胞中急性HIV-1复制的调节作用的信息，我们研究了细胞因子处理对病毒p24抗原表达的影响。基于使用源自体细胞的单核吞噬细胞的报道，我们假设肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）会上调纯化的小胶质细胞和混合脑细胞培养物中HIV-1（SF162，一种嗜单核细胞株）的表达。这一假设未得到支持。事实上，得到了一个相反的、意想不到的结果；在纯化的小胶质细胞培养物中，TNF-α对HIV-1表达显示出轻微的刺激作用（与对照培养物相比，p24抗原产生增加15%），令人惊讶的是，IL-1β和IL-6具有高度抑制作用（分别抑制HIV表达91%和83%）。与小胶质细胞培养物中的发现相反，TNF-α在混合脑细胞培养物中显著抑制（84%）HIV-1表达，IL-1β也是如此（82%），而IL-6具有中度抑制作用（55%抑制）。为了确定在两种脑细胞感染模型中导致TNF-α产生不同作用的因素，发现与小胶质细胞培养物相比，用TNF-α处理混合脑细胞培养物会释放出大量更多的调节激活正常T细胞表达和分泌的趋化因子（RANTES）和巨噬细胞炎性蛋白-1α，β趋化因子，这些趋化因子被认为具有抗HIV-1作用。因此，这些数据表明促炎细胞因子在中枢神经系统中具有抗HIV-1活性。
