Investigation into the mechanism of gamma interferon-mediated inhibition of Toxoplasma gondii in murine astrocytes
Investigation into the mechanism of gamma interferon-mediated inhibition of Toxoplasma gondii in murine astrocytes
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DOI：
10.1128/iai.68.6.3426-3430.2000
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发表时间：
2000-06-01
影响因子：
3.1
通讯作者：
Weiss, LM
中科院分区：
文献类型：
--
作者：
Halonen, SK;Weiss, LM
弓形虫是一种专性细胞内寄生虫，是艾滋病患者中枢神经系统常见的条件致病菌。干扰素(IFN-γ)单独或与白介素1(IL-1)、白介素6(IL-6)或肿瘤坏死因子α联合应用可显著抑制小鼠星形胶质细胞中弓形虫的生长，提示这些细胞是脑内重要的非免疫效应细胞。研究发现，抑制作用与一氧化氮或色氨酸饥饿机制无关。活性氧中间体和铁剥夺都是干扰素-γ介导的机制，可以对抗其他细胞类型的细胞内寄生虫。从活性氧中间体产生基因缺陷的小鼠(Phox(-/-)小鼠)产生的星形胶质细胞被发现在单独使用干扰素-γ或与其他细胞因子联合刺激时抑制弓形虫的生长。活性氧抑制剂过氧化氢酶、活性氧清除剂甘露醇和硫脲不能逆转干扰素-γ对星形胶质细胞弓形虫的抑制作用，提示干扰素-γ对星形胶质细胞的抑制作用不依赖于活性氧中间体。加入铁盐、柠檬酸铁、硝酸铁或转铁蛋白不能逆转TFN-γ的抑制作用。去铁胺对星形胶质细胞的抑制作用也不明显，提示干扰素-γ的抑制机制不是缺铁所致。干扰素-γ对弓形虫侵袭星形胶质细胞无影响，但在感染后24小时，星形胶质细胞的生长受到明显抑制，速殖子空泡消失，提示干扰素-γ激活的星形胶质细胞可能通过一种未知的机制抑制弓形虫。
Toxoplasma gondii is an obligate intracellular parasite that is a common opportunistic pathogen of the central nervous system in AIDS patients. Gamma interferon (IFN-gamma) alone or in combination with interleukin-1 (IL-1), IL-6, or tumor necrosis factor alpha significantly inhibits the growth of T. gondii in murine astrocytes, suggesting these are important nonimmune effector cells in the brain. Inhibition was found to be independent of a nitric oxide-mediated or tryptophan starvation mechanism. Both reactive oxygen intermediates and iron deprivation are IFN-gamma-mediated mechanisms known to operate against intracellular parasites in other cell types.,Astrocytes generated from mice genetically deficient in the production of reactive oxygen intermediates (phox(-/-) mice) were found to inhibit growth of T. gondii when stimulated with IFN-gamma alone or in combination with other cytokines. The reactive oxygen inhibitor catalase and the reactive oxygen scavengers mannitol and thiourea failed to reverse the IFN-gamma-induced inhibition of T. gondii in astrocytes, These data indicate that IFN-gamma-induced inhibition in astrocytes is independent of reactive oxygen intermediates. TFN-gamma-induced inhibition could not be reversed by the addition of iron salts, ferric citrate, ferric nitrate, or ferric transferin. Pretreatment of astrocytes with desferrioxamine also did not induce the inhibition of T, gondii, These data indicate that the mechanism of IFN-gamma inhibition was not due to iron deprivation. IFN-gamma had no effect on T. gondii invasion of astrocytes, but inhibition of growth and loss of tachyzoite vacuoles were evident in IFN-gamma-treated astrocytes by 24 h after invasion, Overall, these data suggest that IFN-gamma-activated astrocytes inhibit T. gondii by an as-yet-unknown mechanism.