TRANSCELLULAR BIOSYNTHESIS OF CYSTEINYL LEUKOTRIENES BY KUPFFER CELL-HEPATOCYTE COOPERATION IN RAT-LIVER

We previously proposed that an enzymatic cooperation between Kupffer c ells and hepatocytes may play an important role in cysteinyl leukotrie ne (LT) production in rat liver. An in vitro transcellular synthesis c ysteinyl LTs by a Kupffer cell-hepatocyte coculture system was charact erized here. Kupffer cells alone, with A23187 stimulation, did not gen erate cysteinyl LTs until supplemented either with isolated hepatocyte s or with LTC(4) synthase and glutathione, indicating that Kupffer cel ls can synthesize LTA(4) but not convert it into LTC(4). In contrast, hepatocytes converted the LTA(4) into cysteinyl LTs and further degrad ed the cysteinyl LTs. Cysteinyl LT production by the Kupffer cell-hapa tocyte coculture system was optimized by addition of 1-3% serum albumi n to the culture and by bringing the cell-cell distance closer to less than 3 mu. Tumour necrosis factor also stimulated cysteinyl LT produc tion by the coculture system. From these results, it is expected that the Kupffer cell-hepatocyte transcellular system for cysteinyl LT prod uction actually functions in vivo. (C) 1996 Academic Press Limited