Gnotobiotic IL-10-/-; NF-κBEGFP Mice Develop Rapid and Severe Colitis Following Campylobacter jejuni Infection
Gnotobiotic IL-10-/-; NF-κBEGFP Mice Develop Rapid and Severe Colitis Following Campylobacter jejuni Infection
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DOI：
10.1371/journal.pone.0007413
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发表时间：
2009-10-20
期刊：
影响因子：
3.7
通讯作者：
Jobin, Christian
中科院分区：
文献类型：
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作者：
Lippert, Elisabeth;Karrasch, Thomas;Jobin, Christian
关于空肠弯曲菌(C.jejui)引起食源性腹泻疾病的分子机制，现有的信息有限。在这项研究中，我们研究了TLR/NF-kappa B信号在空肠弯曲菌诱导的空肠弯曲菌致病机制中的作用。体外分析表明，空肠弯曲菌诱导感染小鼠结肠上皮细胞CMT93的I-kappa B磷酸化，进而增强其转录活性，增加IL-6、MIP-2α和NOD2mRNA的积聚。重要的是，这些事件被IKB抑制剂(Ad5I Kappa BAA)的分子传递所阻断。NF-kappa B信号在空肠弯曲菌诱导的骨髓来源树突状细胞中细胞因子基因表达中也起重要作用。重要的是，根据结肠镜和组织学分析，空肠弯曲菌相关的IL-10(-/-)；NF-kappa B EGFP小鼠出现轻度(第5天)和重度(第14天)溃疡性结肠炎和血性腹泻。宏观分析显示，空肠弯曲菌相关的IL-10(-/-)；NF-kappa B EGFP小鼠的EGFP表达增加，表明NF-kappa B在整个结肠组织中都处于激活状态，而荧光显微镜下显示，EGFP阳性细胞仅位于固有层单核细胞中。BAY 11-7085对NF-kappaB的药理抑制不能减轻空肠弯曲菌引起的结肠炎。我们的发现表明，空肠弯曲菌在易感宿主中诱导快速而严重的肠道炎症，这与固有层免疫细胞增强的核因子-kappa B活性有关。
Limited information is available on the molecular mechanisms associated with Campylobacter jejuni (C. jejuni) induced food-borne diarrheal illnesses. In this study, we investigated the function of TLR/NF-kappa B signaling in C. jejuni induced pathogenesis using gnotobiotic IL-10(-/-); NF-kappa B EGFP mice. In vitro analysis showed that C. jejuni induced I kappa B phosphorylation, followed by enhanced NF-kappa B transcriptional activity and increased IL-6, MIP-2 alpha and NOD2 mRNA accumulation in infected-mouse colonic epithelial cells CMT93. Importantly, these events were blocked by molecular delivery of an IkB inhibitor (Ad5I kappa BAA). NF-kappa B signalling was also important for C. jejuni-induced cytokine gene expression in bone marrow-derived dendritic cells. Importantly, C. jejuni associated IL-10(-/-); NF-kappa B EGFP mice developed mild (day 5) and severe (day 14) ulcerating colonic inflammation and bloody diarrhea as assessed by colonoscopy and histological analysis. Macroscopic analysis showed elevated EGFP expression indicating NF-kappa B activation throughout the colon of C. jejuni associated IL-10(-/-); NF-kappa B EGFP mice, while fluorescence microscopy revealed EGFP positive cells to be exclusively located in lamina propria mononuclear cells. Pharmacological NF-kappa B inhibition using Bay 11-7085 did not ameliorate C. jejuni induced colonic inflammation. Our findings indicate that C. jejuni induces rapid and severe intestinal inflammation in a susceptible host that correlates with enhanced NF-kappa B activity from lamina propria immune cells.