The Role of the Tumor Necrosis Factor Receptor in 2,4,6-Trinitrobenzene Sulphonic Acid (TNBS)-induced Colitis in Mice

众所周知，肿瘤坏死因子（TNF）在炎症性肠病（IBD）的免疫发病机制中起着关键作用，但其机制尚未明确。为了阐明TNF受体在IBD中的作用，我们使用野生型（WT）、TNFR-1 KO、TNFR-2KO和TNFR-1，2KO C57 BL/6品系小鼠研究了给予含有2，4，6-三硝基苯磺酸（TNBS）的灌肠剂的效果，TNBS产生许多与克罗恩病相似的组织学和免疫学状况。用6 mg TNBS经肛门灌洗小鼠结肠，一周后处死。在组织学评估中，所有TNBS给药组之间的炎症细胞评分均无显著差异，而TNFR-1 KO和TNFR-1，2KO小鼠的组织损伤评分显著低于WT小鼠。通过TUNEL染色评估的所有TNBS给药组固有层中单核细胞的凋亡指数显著低于对照组。所有TNBS给药组的血清TNF水平与对照组无显著差异，而结肠中TNF-α mRNA表达在所有TNBS给药组中显著高于对照组。此外，与对照小鼠相比，WT和TNFR-2KO小鼠中的NF-κ B活性增强。总之，目前的数据表明，炎症细胞的持续浸润是基本上负责TNBS-结肠炎在小鼠中的发病机制，这是密切相关的固有层单核细胞的凋亡缺陷，但不与TNF/TNFR信号系统。

It is well known that tumor necrosis factor (TNF) plays a key role in the immunopathogenesis of inflammatory bowel disease (IBD) ; the mechanism, however, has not yet been defined. To elucidate the role of the TNF receptor in IBD, we investigated the effect of administering an enema containing 2,4,6-trinitrobenzene sulphonic acid (TNBS), which produces many histological and immunological conditions similar to those of Crohn's disease, using wild (WT), TNFR-1KO, TNFR-2KO and TNFR-1,2KO C57BL/6 strain mice. Mice were irrigated with 6 mg of TNBS into the colon via the anus and sacrificed one week later. In the histological assessment, inflammatory cell scores showed no significant differences among all TNBS-administered groups, whereas tissue damage scores were significantly lower in TNFR-1KO and TNFR-1,2KO mice than in WT mice. The apoptotic indexes of mononuclear cells in the lamina propria of all TNBS-administered groups assessed by TUNEL straining were significantly lower than that of controls. Serum TNF levels of all TNBS-administered groups did not differ significantly from that of, controls, whereas TNF-a mRNA expression in the colon was significantly higher in all TNBS-administered groups than in controls. Further, NF-kb activities were enhanced in WT and TNFR-2KO mice compared with those in control mice. In conclusion, the present data suggest that continuous infiltration of inflammatory cells is substantially responsible for the pathogenesis of TNBS-colitis in mice, which is closely associated with defective apoptosis of mononuclear cells in the lamina propria but not with the TNF/TNFR signaling system.