Induction by interleukin 6 of Gs-coupled prostaglandin E2 receptors in rat hepatocytes mediating a prostaglandin E2-dependent inhibition of the hepatocyte’s acute phase response

Abstract

Prostanoids, that are released from nonparenchymal liver cells in response to proinflammatory stimuli, are involved in the regulation of hepatic functions during inflammation. They exert their effects on their target cells via heptahelical receptors in the plasma membrane. For the 5 prostanoids prostaglandin E₂ (PGE₂), prostaglandin F_2α, prostaglandin D₂(PGD₂), prostacyclin, and thromboxane A₂ there exist 8 receptors that are coupled to different heterotrimeric G proteins. These receptors are expressed differentially in the 4 principal liver cell types, i.e., hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells. It was intriguing, that the messenger RNA (mRNA) of none of the G_s-coupled prostanoid receptors (DP-R, EP2-R, EP4-R, and IP-R) that can attenuate the inflammatory reaction were present in hepatocytes. The current study shows that the expression of the G_s-coupled prostanoid receptors EP2-R, EP4-R, and DP-R, but not the IP-R, was efficiently and rapidly up-regulated by treatment of hepatocytes in vitro or rats in vivo with the key acute phase cytokine interleukin 6 (IL-6). In IL-6-treated hepatocytes PGE₂ in turn attenuated the IL-6-induced α₂-macroglobulin formation via a cyclic adenosine monophosphate (cAMP)-dependent signal chain. The data indicate that an IL-6-mediated induction of the previously not expressed EP2-R and EP4-R on hepatocytes might establish a prostanoid-mediated feedback inhibition loop for the attenuation of the acute phase response.