Lu H, Yang X, Takeda K, Zhang D, Fan Y, Luo M, Shen C, Wang S, Akira S, Brunham R C
University of British Columbia, Centre for Disease Control, Vancouver, Canada.
Mol Med. 2000 Jul;6(7):604-12.
Interferon (IFN)-gamma is a key to protective immunity against a variety of intracellular bacterial infections, including Chlamydia trachomatis. Interleukin (IL)-18, a recently identified Th1 cytokine, together with IL-12 is a strong stimulator for IFN-gamma production. We investigated the relative roles of IL-18 and IL- 12 in protective immunity to C. trachomatis mouse pneumonitis (MoPn) infection using gene knockout (KO) and wild-type (WT) mice.
Mice were intranasally infected with C. trachomatis MoPn and protective immunity was assessed among groups of mice by daily body weight changes, lung growth of MoPn, and histopathological appearances at day 10 postinfection. The corresponding immune responses for each group of mice at the same postinfection time point were evaluated by measuring antigen-specific antibody isotype responses and cytokine profiles.
Our results showed that IL-18 deficiency had little or no influence on clearance of MoPn from the lung, although KO mice exhibited slightly more severe inflammatory reactions in lung tissues, as well as reduced systemic and local IFN-gamma production, compared with WT mice. Results with IL-18 KO mice were in sharp contrast to those observed with IL-12 KO mice that showed substantially reduced clearance of MoPn from the lungs, substantial reductions of antigen-specific systemic and lung IFN-gamma production, decreased ratio of MoPn-specific immunoglobulin G (IgG)2a/IgG1, and severe pathological changes in the lung with extensive polymorphonuclear, instead of mononuclear, cell infiltration. Exogenous IL-12 or IL-18 was able to increase IFN-gamma production in IL-18 KO mice; whereas, only exogenous IL-12, but not IL-18, enhanced IFN-gamma production in IL-12 KO mice. Caspase-1 is the key protease for activation of IL-18 precursor into the bioactive form, and caspase-1 KO mice also displayed similar bacterial clearance and body weight loss to that in WT mice at early stages of MoPn infection. This further confirmed that IL-18 was not essential for host defense against chlamydia infection.
These results suggest that IL-12, rather than IL-18, plays the dominant role in the development of protective immunity against chlamydia lung infection, although both cytokines are involved in the in vivo regulation of IFN-gamma production.
干扰素（IFN）-γ是抵抗包括沙眼衣原体在内的多种细胞内细菌感染的保护性免疫的关键。白细胞介素（IL）-18是一种最近发现的Th1细胞因子，与IL-12一起是IFN-γ产生的强刺激剂。我们使用基因敲除（KO）和野生型（WT）小鼠研究了IL-18和IL-12在沙眼衣原体小鼠肺炎（MoPn）感染的保护性免疫中的相对作用。
小鼠经鼻内感染沙眼衣原体MoPn，并通过每日体重变化、MoPn在肺中的生长情况以及感染后第10天的组织病理学表现来评估各组小鼠的保护性免疫。在相同的感染后时间点，通过测量抗原特异性抗体亚型反应和细胞因子谱来评估每组小鼠的相应免疫反应。
我们的结果表明，IL-18缺陷对MoPn从肺中的清除几乎没有影响，尽管与WT小鼠相比，KO小鼠在肺组织中表现出稍严重的炎症反应，以及全身和局部IFN-γ产生减少。IL-18 KO小鼠的结果与IL-12 KO小鼠的结果形成鲜明对比，IL-12 KO小鼠显示出MoPn从肺中的清除显著减少，抗原特异性全身和肺IFN-γ产生大幅降低，MoPn特异性免疫球蛋白G（IgG）2a/IgG1的比例降低，以及肺中出现严重的病理变化，伴有广泛的多形核细胞而非单核细胞浸润。外源性IL-12或IL-18能够增加IL-18 KO小鼠中IFN-γ的产生；然而，只有外源性IL-12而非IL-18能增强IL-12 KO小鼠中IFN-γ的产生。半胱天冬酶-1是将IL-18前体激活为生物活性形式的关键蛋白酶，半胱天冬酶-1 KO小鼠在MoPn感染早期也表现出与WT小鼠相似的细菌清除和体重减轻。这进一步证实了IL-18对宿主抵抗衣原体感染并非必不可少。
这些结果表明，尽管两种细胞因子都参与体内IFN-γ产生的调节，但IL-12而非IL-18在针对衣原体肺部感染的保护性免疫发展中起主导作用。
