Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes

Interleukin (IL)-2 administration has been shown to decrease CYP3A enzyme activity in vivo. To determine whether IL-2 suppression of human hepatocyte CYP3A activity is direct or whether it is facilitated by the presence of Kupffer cells, primary human hepatocytes were cultured alone or cocultured with primary human Kupffer cells at physiologic hepatocyte/Kupffer cell ratios of 10:1 or 10:4. Using proinflammatory cytokines as positive controls, IL-1 (0.2-20 ng/ml) and IL-6 (2-200 ng/ml) exposure resulted in a 70 to 90% decrease in CYP3A activity after 72 h in hepatocyte cultures. In the hepatocyte/Kupffer cell cocultures, an 80% decrease in CYP3A activity was observed with IL-1 (2 ng/ml) or IL-6 (20 ng/ml), suggesting that direct suppressive effects of proinflammatory cytokines on hepatocyte CYP3A activity are not substantially altered by Kupffer cells. In contrast to the effects of these proinflammatory cytokines, no sustained suppression of CYP3A activity was observed with IL-2 (2-200 ng/ml) in hepatocyte cultures. However, in hepatocyte/Kupffer cell cocultures, a concentration-dependent 50 to 70% suppression of CYP3A activity was observed with IL-2 at 72 h. In summary, these data suggest that Kupffer cells are required to reconstitute the suppressive effects of IL-2 on CYP3A activity that are observed in vivo and that hepatocyte/Kupffer cell cocultures may provide a useful model for investigating mechanisms of CYP3A4 regulation by cytokines. Of particular relevance to certain hepatic diseases, these findings suggest potential mechanisms whereby cytokines released from infiltrating blood mononuclear cells might modulate intercellular signaling and controls on hepatocyte function by various cell types that reside in liver.