Interferon-γ production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18
Interferon-γ production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18
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DOI：
10.1016/j.micinf.2004.01.003
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发表时间：
2004-04-01
影响因子：
5.8
通讯作者：
Saito, A
中科院分区：
文献类型：
--
作者：
Kawakami, K;Kinjo, Y;Saito, A
干扰素（IFN）-γ在宿主防御结核分枝杆菌感染中起重要作用，其合成受白细胞介素（IL）-12、IL-18和最近鉴定的IL-23的关键调节。本研究旨在确定这些细胞因子在IFN-γ介导的宿主防御M。结核为此，我们比较了IL-12 p40和IL-18双敲除（DKO）小鼠（既缺乏IL-12/IL-18，也缺乏IL-23）和IFN-γ基因破坏（GKO）小鼠的宿主保护性反应。DKO小鼠比GKO小鼠对感染更具抵抗力，如它们延长的存活期和脾、肝和肺中活菌落数减少所示。在DKO小鼠中，通过ELISA在肝和肺匀浆中检测到IFN-γ，但在脾和血清中未检测到IFN-γ，并且通过RT-PCR在所有器官中检测到IFN-γ，其水平与野生型小鼠相当或降低。IFN-γ的产生减少的CD 4 + T细胞的耗竭，但不自然杀伤细胞（NK），NKT，γ δ T和树突状细胞。通过特异性单克隆抗体（mAb）中和IFN-γ或TNF-α显著缩短了受感染的DKO小鼠的存活时间。此外，抗TNF-α mAb部分减弱了这些小鼠肝脏中IFN-γ的合成。最后，诱导型一氧化氮合酶（iNOS）mRNA的表达水平在脾脏，肝脏和肺是相当大的DKO小鼠，但只有边缘或未检测到GKO小鼠。我们的研究结果表明，IL- 12-，IL-18-和IL-23-独立的主机保护性反应的存在下，对分枝杆菌感染介导的IFN-γ，这是分泌的辅助T细胞。(C)2004年，Elsevier SAS。All rights reserved.
Interferon (IFN)-gamma plays an essential role in host defense against infection with Mycobacterium tuberculosis, and its synthesis is critically regulated by interleukin (IL)-12, IL-18 and the recently identified IL-23. The present study was designed to determine the roles of these cytokines in IFN-gamma-mediated host defenses against M. tuberculosis. For this purpose, we compared host protective responses in IL-12p40 and IL-18 double-knockout (DKO) mice (which lacked both IL-12/IL-18 and also IL-23) and IFN-gamma gene-disrupted (GKO) mice. DKO mice were more resistant to the infection than GKO mice, as indicated by their extended survival and reduced live colony numbers in spleen, liver and lung. IFN-gamma was detected by ELISA in liver and lung homogenates, but not in spleen and serum, and in all organs by RT-PCR in DKO mice at comparable or reduced levels to those in wild-type mice. IFN-gamma production was reduced by depletion of CD4+ T cells, but not of natural killer (NK), NKT, gammadeltaT and dendritic cells. Neutralization of IFN-gamma or TNF-alpha by specific monoclonal antibodies (mAbs) significantly shortened the survival time of the infected DKO mice. Furthermore, anti-TNF-alpha mAb partially attenuated IFN-gamma synthesis in the liver of these mice. Finally, the expression level of inducible nitric oxide synthase (iNOS) mRNA in the spleen, liver and lung was considerable in DKO mice but only marginal or undetected in GKO mice. Our results indicate the presence of IL- 12-, IL-18- and IL-23-independent host protective responses against mycobacterial infection mediated by IFN-gamma, which was secreted from helper T cells. (C) 2004 Elsevier SAS. All rights reserved.