Suppression of hepatic lymphokine-activated killer cell induction by murine kupffer cells and hepatocytes

Abstract

Murine lymphokine-activated-killer cell activity was readily induced by culturing spleen cells with 10 U/ml of interleukin-2 for 4 days. In contrast, very little activity was generated under the same culture conditions when nonparenchymal liver cells were used as the responding cells. It was concluded that Kupffer cells produced prostaglandin and interferon α/β, which suppressed lymphokine-activated-killer induction because (a) induction of lymphokine-activated-killer activity from nonparenchymal liver cells was observed in the presence of indomethacin and anti-interferon α/β antibody; (b) when adherent nonparenchymal liver cells, primarily Kupffer cells, were removed, lymphokine-activated-killer activity could be obtained with interleukin-2 alone; (c) coculture of Kupffer cells with nonadherent nonparenchymal liver cells in a two-chambered system inhibited lymphokineactivated killer cell induction in a dose-dependent manner; (d) exogenous prostaglandin E₂ and interferon α/β added at the start of culture inhibited interleukin-2—induced cytotoxicity and proliferation, whereas the other major prostaglandin species in the liver, prostaglandin D₂, had little effect. These findings are distinctive with Kupffer cells because splenic macrophages did not exert such inhibition in parallel experiments. Moreover, the supernatant collected from the 24-hr culture of nonparenchymal liver cells contained greater than 20-fold more prostaglandin E₂ and interferon α/β than that from culture of spleen cells. In subsequent in vivo experiments, when interleukin-2 was given intraperitoneally to mice, the combination of indomethacin and anti-interferon α/β antibody significantly enhanced lymphokine-activated-killer activity recovered from the liver. Besides Kupffer cells, it was found that hepatocytes, the major cellular component of the liver, also played an inhibitory role on lymphokine-activated-killer cell generation. A cell-free liver cytosolic extract had even more potent suppressive effect, which was partially reversed by supplementation of arginine, indicating that arginase may be one of the hepatocyte-derived immunoinhibitors. (HEPATOLOGY 1990;12:644-652).