Differential Effects of Histamine Receptor Antagonists on Human Natural Killer Cell Activity

Abstract

In this study we investigated the modulation of natural killer (NK) cell activity by various histamine receptor antagonists in vitro. The histamine H₂-receptor antagonists cimetidine, ranitidine and tiotidine suppressed NK cell cytotoxicity (NKCC) at a high concentration (10^––3M). Cimetidine enhanced NKCC of Ficoll-Hypaque-separated lymphocytes and of lymphocytes enriched for NKCC by Percoll density gradient centrifugation. The enhancing effect of cimetidine was dose-dependent at final concentrations of 10^––4––10^––7M and did not require the presence of adherent cells/monocytes. Ranitidine did not affect NKCC over a wide range of concentrations. Tiotidine strongly enhanced NKCC of low-density, large granular lymphocyte-enriched mononuclear cells (MNC) in the presence of adherent cells/monocytes, but was ineffective in nonadherent effector cells. All H₂-receptor antagonists clearly antagonized histamine-induced NKCC enhancement in monocyte-containing effector cells. Clemastin, a specific H₁-receptor antagonist, effectively suppressed NKCC. This effect was mimicked by a clemastin isomer with very low affinity for H₁ receptors. We conclude that (1) cimetidine enhances NKCC in vitro by a mechanism of action that is not specifically related to antagonism of H₂-receptors, (2) tiotidine displays mixed agonist/antagonist properties for MNC H₂-receptors and (3) NK-suppressive properties of clemastin are unrelated to H₁-receptor antagonism.