Enteric endotoxine as a intrinsic humoral factor and environmental stress

人们早就知道，在非炎症性、生理/心理应激时，如制动(1MB)和足部电击时，血浆白细胞介素6(IL-6)水平会升高。(FS)我们先前证明，IMB诱导的大鼠血浆IL-6升高至少部分是由肠道菌群衍生的脂多糖(LPS)诱导的肝网状内皮细胞分泌IL-6增加所致。这项研究调查了这种肠道菌群衍生的内毒素是否也可以在到达肝脏之前在肠系膜和肠系膜淋巴结节(MLN)产生IL-6。我们发现在FS期间，肝门静脉(PV)中IL-6水平在30分钟内升高，而颈静脉中IL-6水平上升幅度较小且延迟，恢复较慢。下腔静脉肝静脉出口附近的血浆IL-6水平在对照组和应激状态下均高于门静脉和其他肝外循环。注射多粘菌素B后，应激诱导的IL-6水平升高可被体内中和内毒素所消除。此外，在FS开始后15min内，肠系膜、下丘脑和肝脏中的内毒素含量迅速增加。回肠腔内可见荧光染料标记的脂多糖注入肠外组织和全身静脉，FS能增加回肠腔的光密度。这些结果表明，这些淋巴器官在基础状态下持续暴露于内毒素，FS促进了内毒素/细菌跨肠壁的移位，从而在内毒素到达肝脏之前增加了肠相关淋巴器官中IL-6的产生。此外，我们在本项目中阐明了内毒素对垂体细胞、DNA氧化损伤等的作用。我们可以总结的是，内毒素是建立和保持宿主防御机制的关键中介，就像一种内在的体液因素。

It has long been known that plasma intereukin (IL)-6 levels elevate during non inflammatory, physico/ psychological stresses such as immobiliztion (1MB) and electric foot shock. (FS) We previously demonstrated that an IMB-induced rise in plasma IL-6 in the rat was caused, at least partly, by an increased production of IL-6 in hepatic reticuloendothelial cells which were induced by enteric flora derived lipopolysccharide (LPS). This study investigated whether such enteric flora-derived LPS may produce IL-6 also in the mesentery and the mesenteric lymphoid nodes (MLN) before it reaches the liver. We found a rise in the IL-6 levels in the hepato- portal vein (PV) within 30 min during FS, while the IL-6 levels in thejugular vein showed a smaller and delayed rise with slower recovery. Plasma IL-6 levels near the exit of the hepatic vein in the inferior vena cava was highest at both control and stressed conditions, compared with those in the PV and any other extra-hepatic circulation. The stress-induced IL-6 elevation in the PV was abolished by an in vivo neutralization of LPS with continuous infusion of polymyxin B. Furthermore, the amount of LPS as assessed by its bioactivity increased rapidly in the mesentery, the MLN and the liver within 15 min after the start of FS. Finally, fluorescent dye-labeled LPS infused into the lumen of the ileum was found in the extraintestinal tissues and systemic vein, and FS increased the optical density. The findings suggest that these lymphoid organs are continuously exposed to LPS at the basal condition and FS facilitates the LPS/bacterial translocation across the intestinal wall and thereby increases the production of IL-6 in the gut associated lymphoid organs before LPS reaches the liver.In addition to this, we claryfied the roles of LPS on pituitary cells, DNA oxidative damages, etc, in this project. We can summarize the LPS act as a key mediator to establish and keep the host-defense mechanism like an intrinsic humoral factor.