Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis
Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis
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DOI：
10.1038/mi.2015.18
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发表时间：
2015-11-01
影响因子：
8
通讯作者：
Chen, G-J
中科院分区：
文献类型：
--
作者：
Ning, C.;Li, Y-Y;Chen, G-J
结肠炎相关性结直肠癌(CAC)是炎症性肠病(IBD)最严重的并发症。补体过度活化参与了IBD的发病机制。然而，它在CAC发展中的作用在很大程度上是未知的。在这里，使用偶氮甲烷(AOM)和葡聚糖硫酸钠(DSS)联合给药诱导的CAC模型，我们证明补体激活是CAC发病所必需的。补体关键成分(如C3、C5或C5a受体)的缺乏导致了AOM/DSS小鼠的肿瘤抑制。机制研究表明，补体消融显著降低了结肠组织中致炎细胞因子IL-1β的水平，而IL-1β主要是由中性粒细胞渗入产生的。IL-1β通过在肠道髓系细胞中诱导IL-17反应促进结肠癌的发生。此外，补体激活产物C5a是中性粒细胞中IL-1β的有效诱导剂，这是补体缺陷小鼠IL-1β水平下调的原因。总体而言，我们的研究提出补体在炎症相关的结直肠癌中的促肿瘤作用，并且针对补体的治疗策略可能对临床上治疗CAC有利。
Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1 beta levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1 beta promoted colon carcinogenesis by eliciting IL-17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1 beta in neutrophil, accounting for downregulation of IL-1 beta levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation-related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic.