Enteric endotoxine as a intrinsic humoral factor and environmental stress

长期以来，人们已经知道，血浆白细胞介素（IL）-6水平在非炎症，生理/心理应激，如制动（IMB）和电击脚期间升高。(FS)我们以前证明，IMB诱导的大鼠血浆IL-6升高至少部分是由肠植物群衍生的脂多糖（LPS）诱导的肝网状内皮细胞中IL-6产生增加引起的。本研究调查了这种肠道菌群来源的LPS是否也可以在肠系膜和肠系膜淋巴结（MLN）中产生IL-6，然后到达肝脏。我们发现FS时肝门静脉IL-6水平在30分钟内升高，而颈静脉IL-6水平升高幅度较小且延迟，恢复较慢。与PV和任何其他肝外循环相比，在对照和应激条件下，下腔静脉中肝静脉出口附近的血浆IL-6水平最高。通过体内连续输注多粘菌素B中和LPS，PV中应激诱导的IL-6升高被消除。此外，在FS开始后15分钟内，通过其生物活性评估的LPS的量在肠系膜、MLN和肝脏中迅速增加。最后，在肠外组织和体静脉中发现注入回肠腔的荧光染料标记的LPS，FS使光密度增加。结果表明，在基础状态下，这些淋巴器官持续暴露于LPS，FS促进LPS/细菌的跨肠壁转运，从而在LPS到达肝脏之前增加肠道相关淋巴器官中IL-6的产生，此外，我们还阐明了LPS对垂体细胞、DNA氧化损伤等的作用。LPS作为一种内源性的体液因子，在宿主防御机制的建立和维持中起着重要的介导作用。

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.