Induction by interleukin 6 of G(s)-coupled prostaglandin E-2 receptors in rat hepatocytes mediating a prostaglandin E-2-dependent inhibition of the hepatocyte's acute phase response

Prostanoids, that are released from nonparenchymal liver cells in response to proinflammatory stimuli, are involved in the regulation of hepatic funct ions during inflammation. They exert their effects on their target cells vi a heptahelical receptors in the plasma membrane. For the 5 prostanoids pros taglandin E-2 (PGE(2)), prostaglandin F-2 alpha, prostaglandin D-2 (PGD(2)) , prostacyclin, and thromboxane A(2) there exist 8 receptors that are coupl ed to different heterotrimeric G proteins. These receptors are expressed di fferentially in the 4 principal liver cell types, i.e., hepatocytes, Kupffe r cells, sinusoidal endothelial cells, and hepatic stellate cells. It was i ntriguing, that the messenger RNA (mRNA) of none of the G(s)-coupled prosta noid receptors (DP-R, EP2-R, EP4-R, and IP-R) that can attenuate the inflam matory reaction were present in hepatocytes. The current study shows that t he 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 az-macroglobulin formation via a cyclic adenosine monopho sphate (cAMP)-dependent signal chain. The data indicate that an IL-6-mediat ed induction of the previously not expressed EP2-R and EP4-R on hepatocytes might establish a prostanoid-mediated feedback inhibition loop for the att enuation of the acute phase response.