IL-10 and the dangers of immune polarization: Excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis
IL-10 and the dangers of immune polarization: Excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis
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DOI：
10.4049/jimmunol.164.12.6406
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发表时间：
2000-06-15
影响因子：
4.4
通讯作者：
Wynn, TA
中科院分区：
文献类型：
--
作者：
Hoffmann, KF;Cheever, AW;Wynn, TA
为了分析有争议的1型和2型细胞因子在血吸虫病发病机制中的作用，我们产生了IL-10M-4和IL-10/IL-12缺陷小鼠，它们分别产生了高度极化的1型和2型细胞因子反应。有趣的是，Th1极化的IL-10/IL-4缺陷小鼠在产卵开始时体重迅速下降，并在感染后第9周显示出100%的死亡率。这种急性死亡与促炎介质干扰素-γ、肿瘤坏死因子-α和诱导型一氧化氮的过度表达以及非纤维性肉芽肿的形成有关。血清天冬氨酸转氨酶水平的升高证实了死亡率的部分原因是急性肝毒性，相反，Th2极化的IL-10/IL-12缺陷小鼠发展为进行性消瘦疾病，与肝纤维化增加有关，形成大量富含嗜酸性粒细胞的肉芽肿，IL-4和IL-13增加10倍，并在慢性感染阶段显著死亡。令人惊讶的是，IL-10缺乏的小鼠表现出这两个极端的病理特征，而野生型小鼠发展成相对成功的长期慢性感染。这些数据表明，IL-10显著抑制IL-4和IL-12缺陷小鼠的1型和2型细胞因子的发展，从而阻止单一细胞因子缺陷动物发生严重的卵子诱导的病理。综上所述，这些发现揭示了IL-10在血吸虫病发病机制中的中心调节作用，并说明了过度的1型和2型细胞因子反应在感染后触发了不同的、但同样有害的病理形式。
To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10m-4 and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-gamma, TNF-alpha, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity, In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a l0-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological Features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.