title: Gut-derived norepinephrine plays an important role in up-regulating IL-1beta and IL-10.
abstract: 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-alpha expression in Kupffer cells (KC) via an alpha(2)-adrenoceptor (alpha(2)-AR) pathway. However, it remains unknown whether NE affects the release of other inflammatory cytokines such as IL-1beta and IL-10 and, if so, whether alpha(2)-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 muM in ascorbate saline), NE plus yohimbine (YHB, a specific alpha(2)-AR antagonist, 1 mM) or vehicle (0.1% ascorbate saline) was infused at a rate of 13 mul/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-1beta 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 muM). The gene expression of IL-1beta and IL-10 in KC and their supernatant levels were assessed. The results indicate that serum levels of IL-1beta and IL-10 increased significantly after the intraportal infusion of NE. Co-administration of NE and YHB, however, significantly attenuated IL-1beta and IL-10 production. Similarly, IL-1beta 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-1beta and IL-10 expression and release in the liver through an alpha(2)-AR pathway. Since adenylate cyclase activator forskolin prevents the increase in NE-induced IL-1beta 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.
authors.affiliation: Division of Surgical Research, Department of Surgery, North Shore University Hospital, Manhasset, NY 11030, USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Padmalaya
authors.initials: P
authors.lastname: Das
authors.forename: H Hank
authors.initials: HH
authors.lastname: Simms
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers; D004064:Digestive System / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D018674:Adrenergic Antagonists; D017931:DNA Primers; D007375:Interleukin-1; D016753:Interleukin-10; D015016:Yohimbine; D009638:Norepinephrine