Fischer H G, Nitzgen B, Reichmann G, Hadding U
Institut für Medizinische Mikrobiologie und Virologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Eur J Immunol. 1997 Jun;27(6):1539-48. doi: 10.1002/eji.1830270633.
To investigate the role of astroglia in intracerebral immune response to Toxoplasma gondii, astrocytes cultured from mouse brain were inoculated with mouse-virulent or -avirulent toxoplasma strains. In comparison to microglia/ brain macrophages, astrocytes as host cells allowed stronger proliferation of avirulent parasites. Toxoplasma infection of astroglia was accompanied by release of interleukin- (IL)1 alpha, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) activity, whereas alternative challenge by lipopolysaccharide (LPS) evoked no IL-1 response and significantly higher titers of IL-6 and GM-CSF. At the mRNA level, both stimuli induced transcription of all three cytokines in astrocytes. Secretion of IL-1 and IL-6 upon infection was triggered by T. gondii brady- and tachyzoites in a time- and dose-dependent manner. Heat killing of parasites, but not an exposure to polymyxin B, abrogated their cytokine-inducing activity, thus indicating that an LPS-independent stimulus is provided by T. gondii. When administered in combination, LPS synergistically augmented the IL-1-inducing effect of toxoplasma infection. In comparison, T. gondii-induced, but not an LPS-triggered, IL-6 response of astrocytes resisted to antagonization with IL-10. The IL-6 response of parasitized astroglia was up-regulated by external tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1, with only TNF-alpha enhancing simultaneous release of IL-1. Substantial secretion of IL-10 and TNF-alpha was detected in T. gondii-infected microglia, but not in astrocyte cultures. A possibly autocrine stimulation of infected astroglia via IL-1 was found to be unlikely, since addition of IL-1 receptor antagonist did not affect the release of IL-6 and GM-CSF while inhibiting these responses in IL-1-treated cells. The findings substantiate a separate, T. gondii-induced pathway of astroglia activation characterized by the release of IL-1 which may drive local inflammatory reaction both at initial infection of the brain and during reactivating toxoplasmosis.
为了研究星形胶质细胞在脑内对刚地弓形虫免疫反应中的作用，将从小鼠脑分离培养的星形胶质细胞接种小鼠强毒株或弱毒株弓形虫。与小胶质细胞/脑巨噬细胞相比，作为宿主细胞的星形胶质细胞能使无毒力的寄生虫更强地增殖。星形胶质细胞感染弓形虫伴随着白细胞介素-（IL）1α、IL-6以及粒细胞/巨噬细胞集落刺激因子（GM-CSF）活性的释放，而脂多糖（LPS）的替代性刺激未引发IL-1反应，但IL-6和GM-CSF的滴度显著更高。在mRNA水平，两种刺激均诱导星形胶质细胞中所有三种细胞因子的转录。感染时IL-1和IL-6的分泌由刚地弓形虫缓殖子和速殖子以时间和剂量依赖的方式触发。寄生虫的热灭活而非多粘菌素B的处理消除了它们的细胞因子诱导活性，因此表明刚地弓形虫提供了一种不依赖LPS的刺激。当联合给予时，LPS协同增强了弓形虫感染诱导IL-1的效应。相比之下，弓形虫诱导的星形胶质细胞IL-6反应（而非LPS触发的反应）对IL-10的拮抗有抗性。被寄生的星形胶质细胞的IL-6反应被外源性肿瘤坏死因子（TNF）-α和转化生长因子（TGF）-β1上调，只有TNF-α增强IL-1的同时释放。在刚地弓形虫感染的小胶质细胞中检测到大量IL-10和TNF-α的分泌，但在星形胶质细胞培养物中未检测到。发现通过IL-1对感染的星形胶质细胞进行自分泌刺激的可能性不大，因为添加IL-1受体拮抗剂不影响IL-6和GM-CSF的释放，同时抑制IL-1处理细胞中的这些反应。这些发现证实了一种由弓形虫诱导的独立的星形胶质细胞激活途径，其特征是IL-1的释放，这可能在脑部初次感染和弓形虫病复发期间驱动局部炎症反应。
