Novel anti-inflammatory functions for endothelial and myeloid cyclooxygenase-2 in a new mouse model of Crohn's disease.
Novel anti-inflammatory functions for endothelial and myeloid cyclooxygenase-2 in a new mouse model of Crohn's disease.
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DOI：
10.1152/ajpgi.00468.2009
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发表时间：
2010-03
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通讯作者：
J. Watanabe;James A. Lin;A. Narasimha;A. Shahbazian;T. Ishikawa;Martín G. Martín-Martín-G.-Martín-2219810849;H. Herschman;S. Reddy
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作者：
J. Watanabe;James A. Lin;A. Narasimha;A. Shahbazian;T. Ishikawa;Martín G. Martín-Martín-G.-Martín-2219810849;H. Herschman;S. Reddy
环氧合酶-2（考克斯-2）是一种重要的炎症调节因子，与包括炎症性肠病（IBD）在内的多种疾病的发展有关。然而，考克斯-2对肠道炎症的调节作用尚不清楚。我们以前报道过，考克斯-2（-/-）小鼠喂食含胆酸盐的高脂肪（CCHF）饮食，由于回盲结肠连接处的严重肠道炎症（表现出与克罗恩病（CD）相似的特征），导致未知机制的高死亡率。为了进一步表征考克斯-2在肠道炎症中的作用，我们建立了细胞特异性条件性考克斯-2（-/-）小鼠。内皮细胞特异性（考克斯-2（-E/-E））和骨髓细胞特异性（考克斯-2（-M/-M））考克斯-2（-/-）小鼠（而非野生型小鼠）在CCHF饮食下在回肠-盲肠-结肠连接处出现了局部CD样病理学，该病理学与细胞浸润、髓过氧化物酶和IL-5表达增加以及IL-10表达减少相关。与野生型小鼠和考克斯-2（-M/-M）小鼠相比，考克斯-2（-E/-E）小鼠中的CD样病理还伴随细胞因子（IL-6、TNF-α和INF-γ）表达增加。相比之下，考克斯-2（-M/-M）小鼠的回盲结肠炎症与比考克斯-2（-E/-E）小鼠更明显的粒细胞和巨噬细胞浸润相关。接受CCHF饮食的考克斯-2（-ME/-ME）（考克斯-2（-M/-M）x考克斯-2（-E/-E））小鼠在回肠-盲肠-结肠连接处出现CD样病理学，这与接受CCHF饮食的总考克斯-2（-/-）小鼠和接受考克斯-2抑制剂塞来昔布治疗的CCHF饮食的野生型小鼠相似。考克斯-2（-/-）小鼠中饮食介导的回盲结肠炎症的病理学为阐明内皮和髓样考克斯-2的保护作用以及CD的分子发病机制提供了极好的模型系统。
Cyclooxygenase-2 (COX-2) is an important regulator of inflammation implicated in the development of a variety of diseases, including inflammatory bowel disease (IBD). However, the regulation of intestinal inflammation by COX-2 is poorly understood. We previously reported that COX-2(-/-) mice fed a cholate-containing high-fat (CCHF) diet had high mortality of unknown mechanisms attributable to severe intestinal inflammation in the ileo-ceco-colic junction that presented characteristics similar to Crohn's disease (CD). To further characterize the role of COX-2 in intestinal inflammation, we established cell-specific conditional COX-2(-/-) mice. Endothelial cell-specific (COX-2(-E/-E)) and myeloid cell-specific (COX-2(-M/-M)) COX-2(-/-) mice, but not wild-type mice, on the CCHF diet developed localized CD-like pathology at the ileo-ceco-colic junction that was associated with cellular infiltration, increased expression of myeloperoxidase and IL-5, and decreased IL-10 expression. The CD-like pathology in COX-2(-E/-E) mice was also accompanied by increased expression of cytokines (IL-6, TNF-alpha, and INF-gamma), compared with wild-type mice and COX-2(-M/-M) mice. In contrast, the ileo-ceco-colic inflammation in COX-2(-M/-M) mice was associated with more pronounced infiltration of granulocytes and macrophages than COX-2(-E/-E) mice. COX-2(-ME/-ME) (COX-2(-M/-M) x COX-2(-E/-E)) mice on the CCHF diet developed CD-like pathology in the ileo-ceco-colic junction reminiscent of total COX-2(-/-) mice on CCHF diet and wild-type mice on CCHF diet treated with COX-2 inhibitor, celecoxib. The pathology of diet-mediated ileo-ceco-colic inflammation in COX-2(-/-) mice offers an excellent model system to elucidate the protective roles of endothelial and myeloid COX-2 and the molecular pathogenesis of CD.