The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis
The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis
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DOI：
10.4049/jimmunol.174.6.3534
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发表时间：
2005-03-15
影响因子：
4.4
通讯作者：
Ehlers, S
中科院分区：
文献类型：
--
作者：
Hölscher, C;Hölscher, A;Ehlers, S
IL-12是ifn - γ产生的有效诱导剂，并在结核分枝杆菌感染后促进保护性细胞介导的免疫反应。最近，il -12相关的细胞因子IL-27被发现，WSX-1被鉴定为IL-27R复合物的一个组分。为了确定IL-27/WSX-1在结核中的功能意义，我们分析了WSX-1- ko小鼠气溶胶感染结核分枝杆菌后的感染过程和免疫反应。在缺乏WSX-1的情况下，促炎细胞因子TNF和IL-12p40的产生增加导致CD4(+) T细胞活化和ifn - γ产生升高，从而增强巨噬细胞效应功能并减少细菌负荷。这是选择性基因缺陷小鼠株首次显示出比野生型小鼠更高水平的抗结核分枝杆菌感染保护性免疫。然而，伴随增加的慢性炎症反应也加速了感染WSX-1-KO小鼠的死亡。在体外，IL-27诱导活化的腹膜巨噬细胞STAT3磷酸化，抑制TNF和IL-12的产生，表明IL-27可以调节过度炎症的一种新的反馈机制。总之，IL-27既抑制了最佳的抗真菌保护作用，又限制了慢性炎症的病理后遗症。
IL-12 is a potent inducer of IFN-gamma production and promotes a protective cell-mediated immune response after Mycobacterium tuberculosis infection. Recently, the IL-12-related cytokine IL-27 was discovered, and WSX-1 was identified as one component of the IL-27R complex. To determine the functional significance of IL-27/WSX-1 during tuberculosis, we analyzed the course of infection and the immune response in WSX-1-KO mice after aerosol infection with M. tuberculosis. In the absence of WSX-1, an increased production of the proinflammatory cytokines TNF and IL-12p40 resulted in elevated CD4(+) T cell activation and IFN-gamma production, which enhanced macrophage effector functions and reduced bacterial loads. This is the first occasion of a selectively gene-deficient mouse strain showing higher levels of protective immunity against M. tuberculosis infection than wild-type mice. However, a concomitantly increased chronic inflammatory response also accelerated death of infected WSX-1-KO mice. In vitro, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation. In conclusion, IL-27 both prevents optimal antimycobacterial protection and limits the pathological sequelae of chronic inflammation.