It has long been known that plasma interleukin (IL)-6 levels elevate during non-inflammatory, physico/psychological stresses such as immobilization (IMB) 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 reticulo-endothelial 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 hepatoportal vein (PV) within 30 min during FS, while the IL-6 levels in the jugular 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 initiation of FS. Finally, fluorescent dye-labeled LPS infused into the lumen of the ileum was found in the extra-intestinal tissues and systemic vein, and FS increased the optical density in them. The findings suggest that lymphoid tissues in the gut associated lymphoid organs are continuously exposed to LPS at the basal condition, and that FS facilitates the LPS/bacterial translocation across the intestinal wall and thereby increases the production of IL-6 before LPS reaches the liver.