Induction of functional anaphylatoxin C5a receptors on hepatocytes by in vivo treatment of rats with IL-6

In normal rat liver, anaphylatoxin C5a receptors (C5aR) are only expressed by nonparenchymal cells, mainly Kupffer cells and hepatic stellate cells, b ut not by parenchymal cells, i.e., hepatocytes (HC), Nevertheless, C5a stim ulates glucose output by HC. This HC-specific defense reaction is induced i ndirectly via prostanoids secreted by the C5aR-expressing Kupffer cells and hepatic stellate cells. It is shown here that under inflammatory condition s simulated by in vivo treatment of rats with IL-6 C5aR mRNA and protein we re induced in HC in a time-dependent manner. Maximal mRNA and protein expre ssion were observed at 4-8 h and 8-10 h, respectively, after IL-6 injection . The newly expressed receptors were functional, because recombinant rat C5 a significantly activated glycogen phosphorylase in HC isolated from IL-6-t reated but not in HC from control rats. In perfused livers of IL-6-treated animals in contrast to control animals, recombinant rat C5a-induced glucose output was not impaired by inhibition of prostanoid synthesis and function with the cyclooxygenase inhibitor indomethacin and the thromboxane recepto r antagonist daltroban, These results indicate that HC-specific defense rea ctions might be differently regulated under normal and inflammatory conditi ons as shown here for the indirect prostanoid-dependent or direct C5a-induc ed activation of hepatocellular glycogen phyosphorylase and glucose output in control or IL-6-treated rats, respectively.