The mammalian liver possesses the ability to regenerate to its original size after a 70% partial hepatectomy (PHx). The capacity of rat Kupffer cells (KC) isolated at specific intervals following PHx to produce interleukin-1 (IL-1) and prostaglandin E2 (PGE2) in response to endotoxin (LPS) was evaluated in standard RPMI-1640 (1200 microM L-arginine) and arginine-depleted RPMI-1640 (10 microM L-arginine) media. Regenerating liver KC 48-120 hr following PHx responded to LPS with a significantly greater (p less than 0.05) production of IL-1 in standard RPMI-1640. When 10 microM L-arginine RPMI-1640 was used to simulate the high arginase activity low L-arginine levels of the hepatic microenvironment, regenerating liver KC production of IL-1 was further increased (p less than 0.05). During the same time period, regenerating liver KC also produced significantly (p less than 0.01) more PGE2 than sham KC in both high and low arginine media. When the cyclooxygenase inhibitor indomethacin (10 microM) was added to low arginine cultures, the PGE2 production was inhibited, and IL-1 production was upregulated (p less than 0.05). We conclude that during hepatic regeneration KC IL-1 production is elevated but controlled in an autoregulatory fashion by KC PGE2 production.