Dann Sara M, Spehlmann Martina E, Hammond Dustin C, Iimura Mitsutoshi, Hase Koji, Choi Lillian J, Hanson Elaine, Eckmann Lars
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
J Immunol. 2008 May 15;180(10):6816-26. doi: 10.4049/jimmunol.180.10.6816.
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.
由能导致黏附/脱落性损伤的肠道细菌病原体引起的感染是一个全球性的健康问题。利用一种这样的病原体——啮齿柠檬酸杆菌建立的小鼠感染模型，来阐明多效性免疫调节因子白细胞介素-6（IL-6）在感染发病机制中的重要性。感染啮齿柠檬酸杆菌后，结肠上皮细胞和巨噬细胞中IL-6被强烈诱导，且它是有效宿主防御所必需的，因为缺乏IL-6的小鼠在感染后2至3周无法控制细菌数量，并表现出死亡率增加。对于对病原体产生有效的T细胞和B细胞反应，IL-6并非必需，对于诱导参与宿主抗细菌防御的细胞因子干扰素-γ（IFN-γ）或肿瘤坏死因子-α（TNF-α），以及抗菌效应分子一氧化氮（NO），它也不重要。相反，IL-6在黏膜保护中起关键作用，因为其缺失与结肠上皮中明显的感染诱导的细胞凋亡及随后的溃疡形成有关。细胞培养研究证实，IL-6直接保护结肠上皮细胞免受诱导性细胞凋亡，这伴随着一系列编码抗凋亡蛋白基因的表达增加，包括Bcl-x(L)、Mcl-1、cIAP-2和Bcl-3。溃疡似乎在发病机制中很重要，因为细菌优先定位于那些区域，并且化学诱导的结肠溃疡促进细菌定植。此外，溃疡渗出物中可能存在的血液成分，特别是丙氨酸、天冬酰胺和甘氨酸，促进细菌生长。因此，IL-6是宿主抗啮齿柠檬酸杆菌防御的重要调节因子，它通过保护黏膜免受溃疡形成的影响，而溃疡可作为细菌的微生物龛。
