REGULATION OF HUMAN NATURAL CYTO-TOXICITY BY IGG .2. CYCLIC-AMP AS A MEDIATOR OF MONOMERIC IGG-INDUCED INHIBITION OF NATURAL-KILLER CELL-ACTIVITY

In this study we investigated the mechanism of inhibition of NK activity by monomeric IgG (mIgG) and the enhancement of inhibition induced by 3-isobutyl-l-methylxanthine (IBMX) or theophylline (TP) as inhibitors of cyclic nucleotide phosphodiesterase, or by prostaglandin E2 (PGE2) as an activator of adenyl cyclase. Human peripheral blood mononuclear cells (PBMN) and nonadherent lymphocytes (NAL) were treated with various concentrations of mIgG, IBMX, TP, PGE2, either alone, or in combination. The treatments were done before and/or during the cytotoxicity assay against 51chromium-labeled K562 target cells. Combined pretreatment with mIgG and treatment during the assay with IBMX or TP induced much more inhibition than that induced by either treatment alone. At some concentrations of each agent, additive inhibition was observed, whereas at other concentrations, synergistic effects were seen. With the combination of PGE2 and mIgG an additive inhibitory effect could be seen only at very low concentrations of PGE2, due to its strong inhibitory potency. Although endogenous PGE2 released during preincubation at 37.degree.C by adherent PBMN led to some reduction of NK activity, experiments with indomethacin indicated that mIgG-induced inhibition of spontaneous cytotoxicity was not dependent on its presence. The intracellular levels of cyclic AMP in highly purified NK cells were increased after pretreatment with mIgG and even higher levels were measured when IBMX was also added to the effector cells. Taken together, our data provide evidence that mIgG-induced inhibition of NK cells is mediated at least partially by cyclic AMP.