NITRIC-OXIDE SYNTHASE PATHWAY MAY MEDIATE HUMAN NATURAL-KILLER-CELL CYTOTOXICITY

The present study provides evidence that the human natural killer (NK) cell effector mechanism causing target cytolysis has a requirement fo r L-arginine. In a deficient medium (DM) containing only salts, buffer system and glucose, NK cell-mediated cytotoxicity was found to decrea se by 70% as compared to that obtained in a complete medium (CM). Howe ver, adding L-arginine to such DM could restore the activity of NK cel ls to the normal level. Many other components of CM, such as serum, gl utamine and vitamins did not improve NK cell-mediated killing in DM. W hen all amino acids except L-arginine were added to DM only a partial recovery of NK cell functional cytolysis was seen. L-arginine enhanced the NK cell activity in a dose-dependent manner. Additionally, the in hibitor of both inducible and constitutive nitric oxide synthase, N-mo nomethyl-L-arginine (L-NMMA) inhibited NK cytolytic activity in DM sup plemented with L-arginine indicating participation of nitric oxide (NO ). The results also show that the stimulatory effect of L-arginine on human Mt cell-mediated cytotoxicity was accompanied by an increase in NO formation as determined by accumulation of nitrite and citrulline. L-NMMA gave a dose-dependent reduction in NO generation as well. The n itrite and citrulline production dose-dependently correlated with not only the concentration of L-arginine in the cultivation medium, but al so the enhanced NK cell-mediated cytolysis. Taken together, these find ings could define a L-arginine/NO-linked effector mechanism in human N K cells. Nitrite and citrulline were not formed when NK cell-mediated target cell killing took place in a L-arginine-free DM supplemented wi th additives. Thus, it appears as if human NK cells may cause target c ell killing via both NO-dependent and -independent processes.