Recent work has established that Kupffer cell products, including prostaglandins, can act directly on hepatocytes to modify glucose and lipid metabolism. Additionally, prostaglandins can act on Kupffer cells to modify the expression of cytokines. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) stimulate hepatic lipogenesis following in vivo administration. To define the direct effects of these cytokines on lipogenesis in primary culture rat hepatocytes, hepatocytes were cultured in the presence of IL-6 or TNF-alpha for periods of 24--72 h. IL-6 caused an increase in hepatocyte lipogenic capacity (56% increase by 12.5 ng ml(minus sign1) IL-6 after 72 h of cytokine exposure). The increase in cellular lipogenic capacity was confirmed using (3)H2O as the radiotracer. TNF-alpha did not increase the rate of hepatocyte lipogenesis. Neither IL-6 nor TNF-alpha modified rates of lipogenesis upon acute exposure to the cytokine. Misoprostol-free acid (0.1 &mgr;M) acutely increased hepatocyte lipogenic rates by 14% in the presence of glucagon. These results demonstrate that IL-6 can act directly on hepatocytes to induce lipogenic capacity and that E-series prostaglandins can antagonize the acute inhibition of lipogenesis by glucagon. Because IL-6 is produced by Kupffer cells, and its expression is modulated by prostaglandins, the Kupffer cell is a novel target for prostaglandin therapy. Administration of prostaglandins may provide a novel strategy for pharmacologic therapy of disorders of glucose or lipid metabolism.