Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California.
Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California.
Gastroenterology. 2014 Jun;146(7):1752-62.e4. doi: 10.1053/j.gastro.2014.02.010. Epub 2014 Feb 19.
BACKGROUND & AIMS: The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice.
We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT.
After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin β receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon.
Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin β receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation.
炎症性肠病（IBD）的发病机制与黏膜免疫反应失调有关。肿瘤坏死因子（TNF）超家族成员 14（TNFSF14，也称为 LIGHT[与淋巴毒素同源，表达可诱导，并与 HVEM 竞争，HVEM 是 T 淋巴细胞表达的受体]）在 T 细胞上的表达参与其激活；在小鼠 T 细胞中转基因表达 LIGHT 可促进包括肠道在内的多个器官的炎症。我们研究了 LIGHT 在小鼠肠道炎症恢复中的作用。
我们使用 Tnfsf14(-/-)和野生型小鼠研究了 LIGHT 在肠道炎症中的作用。通过将 CD4(+)CD45RB(high)T 细胞转移到 Rag1(-/-)或 Tnfsf14(-/-)Rag1(-/-)小鼠中，或给予 Tnfsf14(-/-)或野生型 C57BL/6J 小鼠葡聚糖硫酸钠，诱导结肠炎。测量体重、收集和测量结肠组织，并进行组织学分析。我们测量了浸润细胞群和细胞因子、趋化因子和 LIGHT 的表达。
在给予葡聚糖硫酸钠后，与对照相比，Tnfsf14(-/-)小鼠的结肠炎更严重，表现为存活率降低、体重迅速下降和组织学评分升高。LIGHT 通过淋巴毒素 β 受体保护小鼠免受结肠炎的影响，并且主要在结肠中的髓样细胞中表达。Tnfsf14(-/-)小鼠的结肠还具有更高水平的先天免疫细胞积累和更高水平的细胞因子，而对照小鼠的结肠则没有。因此，LIGHT 似乎调节了结肠的炎症。
Tnfsf14(-/-)小鼠比对照小鼠发生更严重的结肠炎。LIGHT 通过结肠中的淋巴毒素 β 受体信号传导调节先天免疫反应并介导肠道炎症的恢复。
