Department of Molecular and Medical Pharmacology, Department of Biological Chemistry, Molecular Biology Institute, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Carcinogenesis. 2011 Mar;32(3):417-26. doi: 10.1093/carcin/bgq268. Epub 2010 Dec 14.
Patients with inflammatory bowel diseases are at increased risk for colorectal cancer. Pharmacological inhibition of cyclooxygenase (COX) function exacerbates symptoms in colitis patients. Animal models of colitis using Cox-2-knockout mice and COX inhibitors also indicate that COX-2 has a protective role against colon inflammation. However, because conventional Cox-2 deletion and COX-2 inhibitors eliminate COX-2 function in all cells, it has not been possible to analyze the role(s) of COX-2 in different cell types. Here, we use a Cox-2(flox) conditional knockout mouse to analyze the role of COX-2 expression in distinct cell types in the colon in response to dextran sulfate sodium (DSS)-induced colitis. We generated Cox-2 conditional knockouts in myeloid cells with LysMCre knock-in mice, in endothelial cells with VECadCreERT2 transgenic mice and in epithelial cells with VillinCre transgenic mice. When treated with DSS to induce colitis, both myeloid cell-specific and endothelial cell-specific Cox-2-knockout mice exhibited greater weight loss, increased clinical scores and decreased epithelial cell proliferation after DSS injury when compared with littermate controls. In contrast, epithelial-specific Cox-2 knockouts and control littermates did not differ in response to DSS. These results suggest that COX-2 expression in myeloid cells and endothelial cells, but not epithelial cells, is important for protection of epithelial cells in this murine colitis model.
炎症性肠病患者患结直肠癌的风险增加。环氧化酶 (COX) 功能的药物抑制会使结肠炎患者的症状恶化。使用 Cox-2 基因敲除小鼠和 COX 抑制剂的结肠炎动物模型也表明 COX-2 对结肠炎症具有保护作用。然而，由于常规的 Cox-2 缺失和 COX-2 抑制剂会消除所有细胞中的 COX-2 功能，因此无法分析 COX-2 在不同细胞类型中的作用。在这里，我们使用 Cox-2(flox)条件性敲除小鼠来分析 COX-2 在对葡聚糖硫酸钠 (DSS)诱导的结肠炎的结肠中不同细胞类型中的表达的作用。我们通过 LysMCre 敲入小鼠在髓样细胞中、通过 VECadCreERT2 转基因小鼠在内皮细胞中和通过 VillinCre 转基因小鼠在上皮细胞中生成 Cox-2 条件性敲除。在用 DSS 诱导结肠炎时，与同窝对照相比，髓样细胞特异性和内皮细胞特异性 Cox-2 敲除小鼠在 DSS 损伤后表现出更大的体重减轻、更高的临床评分和降低的上皮细胞增殖。相比之下，上皮细胞特异性 Cox-2 敲除小鼠和对照同窝仔在 DSS 反应中没有差异。这些结果表明，在这种小鼠结肠炎模型中，髓样细胞和内皮细胞中 COX-2 的表达，而不是上皮细胞中 COX-2 的表达，对于保护上皮细胞很重要。
