NITRIC-OXIDE INHIBITS LPS-INDUCED TUMOR-NECROSIS-FACTOR SYNTHESIS IN-VITRO AND IN-VIVO

The effect of nitric oxide (NO) on LPS-stimulated TNF-alpha synthesis has been studied in vitro and in vivo. The synthesis of TNF-alpha in J 774 macrophages stimulated with LPS (0.1 mu g/ml) was increased in con centration-related fashion by NO synthase inhibitor L-NMMA (3-30-300 m u M) and reduced by either L-arginine (3-30-300 mu M) or the NO donor SIN-1 (1-10-100 mu M). The level of TNF-alpha in the serum of LPS-chal lenged rats (6mg/kg/i.p.) was increased in animals pre-treated s.c. wi th L-NMMA (10 and 50mg/kg) and reduced in those given L-arginine (100 and 300mg/kg). These results show a negative feedback mechanism exhibi ted by NO on TNF-alpha synthesis suggesting an important regulatory li nk between NO and TNF-alpha in pathological processes.