*Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway; †Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ‡Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway; §Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway; ‖Department of Pathology and Medical Genetics, St. Olav's University Hospital, Trondheim, Norway; ¶Research Laboratory, Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway; **Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway; and ††Department of Infectious Diseases, St. Olav's University Hospital, Trondheim, Norway.
Inflamm Bowel Dis. 2014 Jun;20(6):995-1003. doi: 10.1097/MIB.0000000000000035.
Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory bowel disease (IBD). Screening TLR3-agonist response in an intestinal epithelial cell line, we found complement factor B mRNA (CFB) potently upregulated and went on to further study localization of complement factor B synthesis and systemic activation of complement in ulcerative colitis and Crohn's disease.
In a transcriptome analysis of poly (I:C) stimulated HT-29 cells, we found CFB highly upregulated downstream of TLR3. We sought to confirm CFB upregulation in a microarray gene expression analysis on colonic biopsies from an IBD population (n = 133). Immunohistochemical staining and in situ hybridization were done to identify cellular sources of factor B and CFB. Systemic complement activation was assessed in plasma (n = 18) using neoepitope-based enzyme linked immunosorbent assay.
CFB mRNA and protein were abundantly expressed in the colonic epithelial cell line, and synthesis enhanced by the poly (I:C) TLR3 ligand. In inflamed versus normal colonic mucosa of ulcerative colitis and Crohn's disease, CFB mRNA was the most significantly overexpressed gene and the mRNA abundance ratio was among the 50 highest. Epithelial cells were the dominating site of factor B expression. Systemic complement activation was significantly higher in active than in nonactive IBD.
This study is the first to link TLR3 to activation of the alternative complement pathway. Complement factor B is potently upregulated locally in IBD in addition to having a possible central role in systemic complement activation. This suggests a prominent role for complement in IBD pathogenesis.
最近的研究将 Toll 样受体 3（TLR3）与炎症性肠病（IBD）的发病机制联系起来。在肠上皮细胞系中筛选 TLR3 激动剂反应时，我们发现补体因子 B mRNA（CFB）被强烈上调，并继续进一步研究溃疡性结肠炎和克罗恩病中补体因子 B 合成的定位和补体的系统激活。
在聚（I：C）刺激的 HT-29 细胞的转录组分析中，我们发现 CFB 在 TLR3 下游高度上调。我们试图在来自 IBD 人群（n = 133）的结肠活检的微阵列基因表达分析中证实 CFB 的上调。免疫组织化学染色和原位杂交用于鉴定因子 B 和 CFB 的细胞来源。使用基于新表位的酶联免疫吸附试验评估血浆中的系统补体激活（n = 18）。
CFB mRNA 和蛋白在结肠上皮细胞系中大量表达，并且聚（I：C）TLR3 配体增强了合成。在溃疡性结肠炎和克罗恩病的炎症与正常结肠黏膜中，CFB mRNA 是表达上调最显著的基因，mRNA 丰度比值属于前 50 个最高的比值之一。上皮细胞是因子 B 表达的主要部位。与非活动 IBD 相比，活动 IBD 中的系统补体激活明显更高。
这项研究首次将 TLR3 与替代补体途径的激活联系起来。补体因子 B 在 IBD 中局部强烈上调，除了在系统补体激活中可能具有核心作用外。这表明补体在 IBD 发病机制中起重要作用。
