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首页> 外文期刊>Infection and immunity >12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis
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12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

机译：白细胞介素12的12 / 15-Lipoxygenase依赖髓样生产对于抵抗慢性弓形体病至关重要

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Interleukin-12 (IL-12) is critical for resistance to Toxoplasma gondii during both the acute and chronic stages of infection. However, the cellular and molecular pathways that regulate IL-12 production during chronic toxoplasmosis are incompletely defined. We recently discovered that 12/15-lipoxygenase (12/15-LOX), which oxidizes unsaturated lipids in macrophages, is a novel and selective regulator of IL-12 production. We now demonstrate the essential role of this enzyme in the chronic phase of toxoplasmosis. Although 12/15-LOX-deficient mice were resistant to acute T. gondii infection, 80% of 12/15-LOX-deficient mice died during chronic toxoplasmosis, compared to no deaths in wild-type controls. The morbidity of chronically infected 12/15-LOX mice was associated with an increase in brain inflammation and parasite burden. These data suggest that the evolution of the immune response to T. gondii is accompanied by an increasing requirement for 12/15-LOX-mediated signaling. Consistent with this conclusion, 12/15-LOX activity was enhanced during chronic, but not acute, toxoplasmosis. Furthermore, the enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis was associated with reduced production of IL-12 and gamma interferon (IFN-γ) that was not evident during acute infection. Importantly, ex vivo IFN-γ production by 12/15-LOX-deficient splenocytes could be rescued by the addition of recombinant IL-12. These data establish that 12/15-LOX is a critical mediator of the chronic type 1 inflammatory response and that immune mediators can be subject to distinct cellular and/or molecular mechanisms of regulation at different stages of inflammation.
机译：白介素12（IL-12）对于在感染的急性和慢性阶段对弓形虫的抵抗力至关重要。但是，在慢性弓形虫病期间调节IL-12产生的细胞和分子途径尚未完全定义。我们最近发现，氧化巨噬细胞中不饱和脂质的12 / 15-脂加氧酶（12 / 15-LOX）是IL-12生产的新型选择性调节剂。现在，我们证明该酶在弓形虫病的慢性期中的重要作用。尽管12 / 15-LOX缺陷型小鼠对急性T细胞有抗性。刚地弓形虫感染后，慢性弓形虫病期间80％的12 / 15-LOX缺陷小鼠死亡，而野生型对照组则无死亡。慢性感染的12 / 15-LOX小鼠的发病率与脑部炎症和寄生虫负担增加有关。这些数据表明对 T的免疫应答的演变。刚地伴随着对12 / 15-LOX介导的信号传导的需求不断增加。与该结论一致，在慢性而非急性弓形体病期间，12 / 15-LOX活性增强。此外，12 / 15-LOX缺陷型小鼠对慢性弓形虫病的易感性增强与IL-12和γ干扰素（IFN-γ）的产生减少有关，这在急性感染中并不明显。重要的是，可以通过添加重组IL-12来挽救12 / 15-LOX缺陷型脾细胞的离体IFN-γ产生。这些数据证实12 / 15-LOX是慢性1型炎症反应的关键介质，并且免疫介质可以在炎症的不同阶段受到不同的细胞和/或分子调节机制的影响。

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