Nottet H S, Jett M, Flanagan C R, Zhai Q H, Persidsky Y, Rizzino A, Bernton E W, Genis P, Baldwin T, Schwartz J
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198.
J Immunol. 1995 Apr 1;154(7):3567-81.
HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-alpha. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus-infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-beta independent. Although astrocytes constitutively produced latent TGF-beta 2, HIV-1-infected monocytes neither affected TGF-beta 2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-beta 1 or rTGF-beta 2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-alpha. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus-infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.
感染HIV-1的脑巨噬细胞通过持续分泌神经毒素参与神经功能障碍。我们之前证明，星形胶质细胞可激活感染HIV-1的单核细胞以产生此类神经毒性活性。在本研究中，这些单核细胞分泌活性的潜在机制得以阐明，发现其依赖于HIV-1使单核细胞致敏以进行激活的能力。用脂多糖（LPS）刺激感染HIV-1的单核细胞会导致类花生酸、血小板活化因子（PAF）和肿瘤坏死因子-α（TNF-α）的过度表达。这取决于HIV-1感染水平和单核细胞刺激情况。活化的病毒感染单核细胞与原代人星形胶质细胞之间的细胞间相互作用减少了单核细胞的分泌。值得注意的是，星形胶质细胞使单核细胞失活的能力不依赖于转化生长因子-β（TGF-β）。尽管星形胶质细胞组成性地产生潜伏性TGF-β2，但感染HIV-1的单核细胞既不影响TGF-β2的产生，也不会将其转化为生物活性分子。此外，向LPS刺激的单核细胞-星形胶质细胞混合物中添加重组人TGF-β1或重组人TGF-β2或其抗体对单核因子的产生没有影响。相反，向LPS刺激的单核细胞中添加重组人白细胞介素-10（rIL-10）会使TNF-α呈剂量依赖性降低。LPS处理后，在单核细胞中检测到IL-10 mRNA，但在星形胶质细胞中未检测到。这些结果表明，巨噬细胞活化是脑内HIV-1感染的一个主要成分，通过使病毒感染细胞合成神经毒素而促成神经元损伤。单核细胞产生的神经毒素随后受到星形胶质细胞的调节。因此，根据先前巨噬细胞的活化情况，星形胶质细胞在疾病中可发挥正向或负向作用。这些发现开始揭示影响HIV-1感染个体认知和运动功能障碍的细胞控制机制。
