IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans
IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans
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DOI：
10.4049/jimmunol.179.8.5367
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Alber, Gottfried
中科院分区：
文献类型：
--
作者：
Mueller, Uwe;Stenzel, Werner;Alber, Gottfried
在新型隐球菌感染的鼠模型中，Th 1（IL-12/IFN-γ）和Th 17（IL-23/IL-17）应答与保护相关，而IL-4依赖性Th 2应答使疾病恶化。为了研究Th 2细胞因子IL-13在新生隐球菌肺部感染过程中的作用，鼻内感染IL-13过表达转基因（IL-13 Tg（+））、IL-13缺陷（IL-13（-/-））和野生型（WT）小鼠。当在WT小鼠中诱导IL-13或在IL-13 Tg（+）小鼠中过度产生IL-13时，发现对新型隐球菌感染的易感性。与WT小鼠相比，感染IL-13 Tg（+）小鼠的存活时间缩短，肺部真菌负荷增加。相比之下，感染的IL-13-/-小鼠具有抗性，并且这些小鼠中的89%在整个实验期间存活。易感WT和IL-13 Tg（+）小鼠产生的Ag特异性IL-13与显著的2型细胞因子变化相关，但IFN-γ产生的变化较小。与增强的2型细胞因子产生一致，在易感WT和IL-13 Tg（+）小鼠中检测到高水平的血清IgE和低血清IgG 2a/IgG 1比值。有趣的是，易感WT和IL-13 Tg（+）小鼠的IL-13表达与IL-17产生减少相关。发现IL-13诱导表达谷胱甘肽转移酶-1、巨噬细胞甘露糖受体（CD 206）和YM 1的交替活化的巨噬细胞的形成。此外，IL-13的产生导致肺嗜酸性粒细胞增多、杯状细胞化生和粘液产生增加，并增强气道高反应性。这表明IL-13在C.新生儿感染。
In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-gamma) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C neoformans, IL-13-overexpressing transgenic (IL-13Tg(+)), IL-13-deficient (IL-13(-/-)), and wild-type (WT) mice were infected intranasally. Susceptibility to C neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg(+)mice. Infected IL-13Tg(+) mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13-/- mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with a significant type 2 cytokine shift but only minor changes in IFN-gamma production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg(+) mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-l, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.