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, People's Republic of China; and.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104;
J Immunol. 2014 Aug 1;193(3):1064-70. doi: 10.4049/jimmunol.1400415. Epub 2014 Jun 27.
Both commensal bacteria and infiltrating inflammatory cells play essential roles in the pathogenesis of inflammatory bowel disease. The molecular mechanisms whereby these pathogenic factors are regulated during the disease are not fully understood. We report in this article that a member of the TNF-α-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) plays a crucial role in regulating commensal bacteria dissemination and inflammatory cell function in experimental colitis induced by dextran sodium sulfate (DSS). Following DSS treatment, TIPE2-deficient mice, or chimeric mice that are deficient in TIPE2 only in their hematopoietic cells, lost less body weight and survived longer than wild-type controls. Consistent with this clinical observation, TIPE2-deficient mice exhibited significantly less severe colitis and colonic damage. This was associated with a marked reduction in the colonic expression of inflammatory cytokines, such as TNF-α, IL-6, and IL-12. Importantly, the ameliorated DSS-induced colitis in TIPE2(-/-) mice also was associated with reduced local dissemination of commensal bacteria and a weaker systemic inflammatory response. Combined with our previous report that TIPE2 is a negative regulator of antibacterial immunity, these results indicate that TIPE2 promotes colitis by inhibiting mucosal immunity to commensal bacteria.
共生菌和浸润性炎症细胞在炎症性肠病的发病机制中都起着至关重要的作用。这些致病因素在疾病过程中是如何被调节的，其分子机制尚不完全清楚。我们在本文中报告称，TNF-α诱导蛋白 8（TNFAIP8）家族的一个成员，称为 TIPE2（TNFAIP8 样蛋白 2），在葡聚糖硫酸钠（DSS）诱导的实验性结肠炎中，对调节共生菌的传播和炎症细胞功能起着至关重要的作用。在 DSS 处理后，TIPE2 缺陷型小鼠或仅在其造血细胞中缺乏 TIPE2 的嵌合小鼠比野生型对照小鼠体重减轻更少，存活时间更长。与这一临床观察一致，TIPE2 缺陷型小鼠表现出明显较轻的结肠炎和结肠损伤。这与结肠中炎症细胞因子（如 TNF-α、IL-6 和 IL-12）的表达显著减少有关。重要的是，TIPE2(-/-) 小鼠中改善的 DSS 诱导的结肠炎也与共生菌局部传播减少和全身炎症反应减弱有关。结合我们之前的报告，即 TIPE2 是抗菌免疫的负调节剂，这些结果表明，TIPE2 通过抑制对共生菌的粘膜免疫来促进结肠炎。
