Gut-derived norepinephrine plays an important role in up-regulating IL-1β and IL-10

Previous studies have shown that the gut is a major source of norepinephrine (NE) released in early sepsis and that gut-derived NE plays an important role in up-regulating TNF-α expression in Kupffer cells (KC) via an α2-adrenoceptor (α2-AR) pathway. However, it remains unknown whether NE affects the release of other inflammatory cytokines such as IL-1β and IL-10 and, if so, whether α2-AR is also involved in such a process. To study this, a branch of the portal vein in normal adult male rats was cannulated under anesthesia. NE (20 μM in ascorbate saline), NE plus yohimbine (YHB, a specific α2-AR antagonist, 1 mM) or vehicle (0.1% ascorbate saline) was infused at a rate of 13 μl/min for 2 h. The above rate of NE infusion was used to increase the portal level of NE to approximately 20 nM, similar to that observed in sepsis. Blood samples were then collected and serum levels of IL-1β and IL-10 were measured. In addition, the KC was isolated from normal rats and stimulated with either NE (20 nM) or NE plus YHB (1 μM). The gene expression of IL-1β and IL-10 in KC and their supernatant levels were assessed. The results indicate that serum levels of IL-1β and IL-10 increased significantly after the intraportal infusion of NE. Co-administration of NE and YHB, however, significantly attenuated IL-1β and IL-10 production. Similarly, IL-1β and IL-10 gene expression and release from KC were up-regulated by NE stimulation, whereas YHB attenuated both cytokines. Thus, gut-derived NE up-regulates IL-1β and IL-10 expression and release in the liver through an α2-AR pathway. Since adenylate cyclase activator forskolin prevents the increase in NE-induced IL-1β and IL-10, the up-regulatory effect of NE on those cytokines appears to be mediated, at least in part, by inhibition of adenylate cyclase and reduction in intracellular cyclic AMP levels.