Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Inflamm Bowel Dis. 2011 Jul;17(7):1464-73. doi: 10.1002/ibd.21527. Epub 2010 Nov 15.
Chronic intestinal inflammation culminates in cancer and a link to Toll-like receptor-4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa.
Mice transgenic for a constitutively active TLR4 under the intestine-specific villin promoter (villin-TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)-DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC-associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis-associated neoplasia in the AOM-DSS model.
Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE₂ production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis-associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model.
Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis-associated cancer.
慢性肠道炎症最终会导致癌症，我们的观察结果表明，Toll 样受体 4（TLR4）的缺失可预防结肠炎相关肿瘤的发生，这提示 TLR4 与之相关。在本研究中，我们研究了上皮 TLR4 的异常激活对诱导结肠炎和结肠炎相关肿瘤发展的影响。我们采用转化方法来研究肠道黏膜中 TLR 信号转导增加的后果。
在肠特异性微绒毛启动子（villin-TLR4 小鼠）下表达组成型激活 TLR4 的小鼠用葡聚糖硫酸钠（DSS）治疗急性结肠炎，并通过免疫组化分析溃疡性结肠炎（UC）患者和 UC 相关癌症患者的结肠组织中 TLR4 的表达。在 AOM-DSS 模型中，检测 TLR4 拮抗剂抗体的预防结肠炎相关肿瘤的效果。
villin-TLR4 小鼠对急性结肠炎和结肠炎相关肿瘤均高度敏感。villin-TLR4 小鼠在基线时具有较高的 COX-2 上皮表达和黏膜 PGE₂ 产生。villin-TLR4 小鼠中结肠炎的严重程度增加的特征为炎症介质表达增强和中性粒细胞浸润增加。在人类 UC 样本中，TLR4 表达在上皮细胞中几乎在所有结肠炎相关癌症中均上调，并且随着异型增生的程度逐渐增加。作为原理的证明，TLR4/MD-2 拮抗剂抗体抑制了小鼠模型中的结肠炎相关肿瘤。
我们的结果表明，TLR 的调节可以影响急性结肠炎及其后果（癌症）的结局。靶向 TLR4 和其他 TLR 最终可能在预防或治疗结肠炎相关癌症中发挥作用。
