Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells

Growing evidence obtained in recent years indicates that anaphylatoxin C5a receptors (C5aR) are not restricted to myeloid cells but are also expressed on nonmyeloid cells in different tissues such as brain, lung, skin and liv er. In contrast to its well-defined systemic functions, the actions of anap hylatoxins in these organs are poorly characterized. The liver can be a pri mary target organ for the C5a anaphylatoxin since the liver is directly con nected to the gut, via the mesenteric veins and portal vein which is a main source of complement activating lipopolysaccharides (LPS). In the normal r at liver, the C5aR is only expressed by nonparenchymal cells, i.e. strongly by Kupffer cells (KC) and hepatic stellate cells (HSC) and weakly by sinus oidal endothelial cells (SEC), bur not expressed by the parenchymal hepatoc ytes (HC). Accordingly, direct effects of C5a were only found in the C5aR-e xpressing KC and HSC: C5a induced thr release of prostanoids from KC and HS C and enhanced the UPS-dependent release of interleukin-6 from KC, These so luble mediators indirectly influenced effector functions of the C5aR-free H C. C5a enhanced the glycogen phosphorylase activity and thus the glucose ou tput from HC indirectly via prostanoids released from KC and HSC. Glucose c an serve as an energy substrate as well as an electron donor for the synthe sis of reactive oxygen intermediates by KC. Moreover, C5a also enhanced tra nscription of the gene for the type-2 acute phase protein alpha (2)-macrogl obulin in HC indirectly by increasing LPS-dependent IL-6 release from KC. U nder pathological conditions. C5aR was found to be upregulated in various o rgans including the liver. Simulation of inflammatory conditions by treatme nt of rats with IL-6, a main inflammatory mediator in the liver, caused a d e novo expression of functional C5aR in HC. In livers of IL-6-treated rats, C5a initiated glucose output from HC and perhaps other HC-specific defense reactions directly without the intervention of soluble mediators from nonp arenchymal cells. (C) 2001 Elsevier Science B.V, All rights reserved.