IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens
IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens
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DOI：
10.4049/jimmunol.180.10.6816
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发表时间：
2008-05-15
影响因子：
4.4
通讯作者：
Eckmann, Lars
中科院分区：
文献类型：
--
作者：
Dann, Sara M.;Spehlmann, Martina E.;Eckmann, Lars
肠道感染与附着/消失病变诱导细菌病原体是一个世界性的健康问题。一个这样的病原体，啮齿类柠檬酸杆菌，小鼠感染模型，用于阐明多效性免疫调节剂，IL-6，在感染的发病机制中的重要性。IL-6在啮齿类念珠菌感染后在结肠上皮细胞和巨噬细胞中被强烈诱导，并且是有效的宿主防御所必需的，因为缺乏IL-6的小鼠在感染后2-3周不能控制细菌数量，并且表现出增加的死亡率。IL-6对T细胞和B细胞对病原体的有效应答是不需要的，对IFN-γ或TNF-α的诱导也不重要，IFN-γ或TNF-α是宿主防御细菌的细胞因子，或抗菌效应物NO。相反，IL-6在粘膜保护中起关键作用，因为它的缺乏与结肠上皮中显著的感染诱导的细胞凋亡和随后的溃疡有关。细胞培养研究证实，IL-6直接保护结肠上皮细胞免于诱导性凋亡，这伴随着编码抗凋亡蛋白的一系列基因的表达增加，包括Bcl-x（L）、Mcl-1、cIAP-2和Bcl-3。溃疡似乎是重要的致病性，因为细菌本地化优先这些地区，化学诱导的结肠溃疡促进细菌定植。此外，可能存在于溃疡渗出物中的血液成分，特别是丙氨酸、天冬酰胺和甘氨酸，促进细菌生长。因此，IL-6是宿主防御C.通过保护粘膜免受溃疡，这可以作为细菌的微生物生态位，从而保护啮齿动物。
Enteric infections with attaching/effacing lesion-inducing bacterial pathogens are a worldwide health problem. A murine infection model with one such pathogen, Citrobacter rodentium, was used to elucidate the importance of the pleiotropic immune regulator, IL-6, in the pathogenesis of infection. IL-6 was strongly induced in colonic epithelial cells and macrophages upon C rodentium infection and was required for effective host defense, because mice lacking IL-6 failed to control bacterial numbers 2-3 wk after infection and exhibited increased mortality. IL-6 was not needed for mounting effective T and B cell responses to the pathogens, nor was it important for induction of IFN-gamma or TNF-alpha, cytokines involved in host defense against the bacteria, or the antibacterial effector, NO. Instead, IL-6 played a key role in mucosal protection, since its absence was associated with marked infection-induced apoptosis in the colonic epithelium and subsequent ulcerations. Cell culture studies confirmed that IL-6 protected colon epithelial cells directly against inducible apoptosis, which was accompanied by increased expression of an array of genes encoding antiapoptotic proteins, including Bcl-x(L), Mcl-1, cIAP-2, and Bcl-3. Ulcerations appeared to be pathogenetically important, because bacteria localized preferentially to those regions, and chemically induced colonic ulcerations promoted bacterial colonization. Furthermore, blood components likely present in ulcer exudates, particularly alanine, asparagine, and glycine, promoted bacterial growth. Thus, IL-6 is an important regulator of host defense against C. rodentium by protecting the mucosa against ulcerations which can act as a microbial niche for the bacteria.