Hörnquist C E, Lu X, Rogers-Fani P M, Rudolph U, Shappell S, Birnbaumer L, Harriman G R
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
J Immunol. 1997 Feb 1;158(3):1068-77.
Mice with targeted deletion of the G protein G(alpha)i2 develop an inflammatory bowel disease closely resembling ulcerative colitis. To better define disease pathogenesis, the mucosal immune system in G(alpha)i2-deficient mice was studied. Phenotypic analysis of large intestine lamina propria lymphocytes revealed a large increase in memory CD4+ T cells (CD44high, CD45RBlow, CD62Llow). Furthermore, expression of the mucosal homing receptor integrin beta7 was increased on mucosal, but not systemic, CD4+ T cells. Analysis of cytokine production revealed a marked increase in proinflammatory Th1-type cytokines in inflamed colons, as compared with wild-type mice or G(alpha)i2-deficient mice without colitis. Thus, IFN-gamma and IL-1beta levels were increased 13-fold and 30-fold, respectively, with more modest increases in IL-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G(alpha)i2-deficient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G(alpha)i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysis to result from local production within the lamina propria.
G蛋白G(α)i2基因靶向缺失的小鼠会患上一种与溃疡性结肠炎极为相似的炎症性肠病。为了更好地明确疾病发病机制，对G(α)i2缺陷小鼠的黏膜免疫系统进行了研究。对大肠固有层淋巴细胞的表型分析显示，记忆性CD4+ T细胞（CD44高、CD45RB低、CD62L低）大幅增加。此外，黏膜归巢受体整合素β7在黏膜而非全身的CD4+ T细胞上表达增加。细胞因子产生分析显示，与野生型小鼠或无结肠炎的G(α)i2缺陷小鼠相比，炎症结肠中促炎性Th1型细胞因子显著增加。因此，IFN-γ和IL-1β水平分别增加了13倍和30倍，IL-6水平（5倍）和TNF水平（2倍）的增加幅度较小。G(α)i2缺陷小鼠的炎症结肠中IL-12 p40 mRNA水平也升高。未观察到IL-2、IL-4、IL-5和IL-10增加。通过免疫组织化学发现，患有结肠炎的G(α)i2缺陷小鼠的大肠上皮细胞中MHC I类和II类抗原的表达水平均增加。结肠炎与大肠而非小肠分泌物中IgG水平升高（增加60倍）有关，主要是IgG2a（增加135倍）。ELISPOT分析表明，这是由固有层内的局部产生所致。
