Sun Honghong, Lou Yunwei, Porturas Thomas, Morrissey Samantha, Luo George, Qi Ji, Ruan Qingguo, Shi Songlin, Chen Youhai H
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104;
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104; Department of Immunology, Shandong University School of Medicine, Ji'nan 250012, China; and.
J Immunol. 2015 Jun 15;194(12):5736-42. doi: 10.4049/jimmunol.1401986. Epub 2015 May 6.
The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiologic and pathologic functions are unclear. In this study, we describe the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs, including lymphoid organs and intestines, were macroscopically and microscopically normal. However, after drinking dextran sodium sulfate-containing water, TIPE-deficient mice developed more severe colitis than wild type mice did, as demonstrated by decreased survival rates, increased body weight loss, and enhanced leukocyte infiltration, bacterial invasion, and inflammatory cytokine production in the colon. Bone marrow chimeric experiments revealed that TIPE deficiency in nonhematopoietic cells was responsible for the exacerbated colitis in TIPE-deficient mice. Consistent with this result, TIPE-deficient intestinal epithelial cells had increased rate of cell death and decreased rate of proliferation as compared with wild type controls. These findings indicate that TIPE plays an important role in maintaining colon homeostasis and in protecting against colitis.
肿瘤坏死因子-α诱导蛋白8（TNFAIP8或TIPE）是癌症和细菌感染的一个风险因素，其表达在多种人类癌症中上调。然而，其生理和病理功能尚不清楚。在本研究中，我们描述了TIPE缺陷小鼠的产生及其对结肠炎症的敏感性增加。通过种系基因靶向产生了TIPE缺陷小鼠，它们出生时没有明显的发育异常。它们的主要器官，包括淋巴器官和肠道，在宏观和微观上都是正常的。然而，饮用含葡聚糖硫酸钠的水后，TIPE缺陷小鼠比野生型小鼠发生更严重的结肠炎，表现为存活率降低、体重减轻增加以及结肠中白细胞浸润、细菌侵袭和炎性细胞因子产生增强。骨髓嵌合实验表明，非造血细胞中的TIPE缺陷是TIPE缺陷小鼠结肠炎加重的原因。与该结果一致，与野生型对照相比，TIPE缺陷的肠上皮细胞细胞死亡率增加而增殖率降低。这些发现表明，TIPE在维持结肠稳态和预防结肠炎中起重要作用。
