Cox-2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis.
Cox-2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis.
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DOI：
10.1093/carcin/bgq268
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发表时间：
2011-03-01
期刊：
影响因子：
4.7
通讯作者：
Herschman, Harvey R.
中科院分区：
文献类型：
--
作者：
Ishikawa, Tomo-o;Oshima, Masanobu;Herschman, Harvey R.
患有炎症性肠病的患者患结直肠癌的风险增加。环氧合酶 (COX) 功能的药理学抑制会加剧结肠炎患者的症状。使用 Cox-2 敲除小鼠和 COX 抑制剂建立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，由于传统的 Cox-2 缺失和 COX-2 抑制剂消除了所有细胞中的 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) 条件敲除小鼠来分析结肠中不同细胞类型中 COX-2 表达对葡聚糖硫酸钠 (DSS) 诱导的结肠炎的作用。我们用 LysMCre 敲入小鼠在骨髓细胞中、用 VECadCreERT2 转基因小鼠在内皮细胞中以及用 VillinCre 转基因小鼠在上皮细胞中产生 Cox-2 条件敲除。当用 DSS 治疗诱导结肠炎时，与同窝对照相比，骨髓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、临床评分增加和上皮细胞增殖减少。相比之下，上皮特异性 Cox-2 敲除和对照同窝小鼠对 DSS 的反应没有差异。这些结果表明，在小鼠结肠炎模型中，骨髓细胞和内皮细胞（而非上皮细胞）中的 COX-2 表达对于保护上皮细胞很重要。
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.