Rudolph U, Finegold M J, Rich S S, Harriman G R, Srinivasan Y, Brabet P, Bradley A, Birnbaumer L
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Clin Immunol. 1995 Nov;15(6 Suppl):101S-105S. doi: 10.1007/BF01540899.
Mice deficient for the G protein subunit Gi2 alpha were obtained by gene targeting. They displayed a growth retardation that was apparent at 6 weeks of age. They subsequently developed diffuse colitis with clinical and histopathological features closely resembling those of ulcerative colitis in humans. Seven of 20 Gi2 alpha-deficient mice with colitis also developed adenocarcinomas of the colon. Gi2 alpha-deficient thymocytes displayed two- to fourfold increases in mature CD4+8- and CD4-8+ phenotypes, an approximately threefold increase in high-intensity CD3 staining and enhanced proliferative responses to T-cell receptor stimuli. Stimulation of Gi 2 alpha-deficient peripheral T cells induced a hyperresponsive profile of interleukin-2, tumour necrosis factor, and interferon-gamma production, which may reflect a heightened response of primed cells or a defective negative regulation. We suggest that Gi 2 alpha-deficient mice may represent a useful animal model for dissecting the pathomechanisms of inflammatory bowel disease and also for the development of novel therapeutic strategies.
通过基因靶向获得了G蛋白亚基Gi2α缺陷的小鼠。它们表现出在6周龄时明显的生长迟缓。随后它们发展出弥漫性结肠炎，其临床和组织病理学特征与人类溃疡性结肠炎极为相似。20只患有结肠炎的Gi2α缺陷小鼠中有7只还发展出了结肠癌。Gi2α缺陷的胸腺细胞在成熟的CD4 + 8 -和CD4 - 8 +表型上增加了两到四倍，高强度CD3染色增加了约三倍，并增强了对T细胞受体刺激的增殖反应。对Gi2α缺陷的外周T细胞的刺激诱导了白细胞介素-2、肿瘤坏死因子和干扰素-γ产生的高反应性谱，这可能反映了致敏细胞反应增强或负调节缺陷。我们认为，Gi2α缺陷小鼠可能是一种有用的动物模型，可用于剖析炎症性肠病的发病机制，也可用于开发新的治疗策略。
