HISTAMINERGIC REGULATION OF INTERFERON-GAMMA (IFN-GAMMA) PRODUCTION BY HUMAN NATURAL-KILLER (NK) CELLS

Monocytes, recovered from human peripheral blood by counter-current ce ntrifugal elutriation, effectively inhibit the production of IFN-gamma by CD3(-)/56(+) NK cells in response to IL-2. This study aimed at def ining the nature of the inhibitory signal, particularly the importance of monocyte-derived reactive metabolites of oxygen. It was found that monocytes recovered from patients with chronic granulomatous disease (CGD), a condition characterized by deficient NADPH-oxidase activity o f phagocytes, did not inhibit IFN-gamma production by NK cells. Furthe r, catalase, a scavenger of hydrogen peroxide, completely reversed the inhibitory signal, whereas scavengers of the superoxide anion, hypoha lous acids, the hydroxyl radical, or nitric oxide synthesis inhibitors such as L-NMMA were ineffective. Inhibition of IFN-gamma production w as operating on a pretranslational level, as indicated by the inabilit y of enriched NK cells to accumulate IFN-gamma mRNA in the presence of elutriated monocytes. Hydrogen peroxide, at micromolar concentrations , reconstituted the inhibition of IFN-gamma production when added to e nriched NK cells. Histamine, a biogenic amine which inhibits the gener ation of reactive oxygen metabolites in monocytes, abrogated the inhib ition of IFN-gamma production in NK cells; by this mechanism, histamin e strongly synergized with IL-2 to induce IFN-gamma in mixtures of NK cells and monocytes. The synergizing effect of histamine was specifica lly mediated by H-2-type histamine receptors. We conclude that: (i) th e induction of IFN-gamma mRNA in NK cells is effectively down-regulate d by products of the oxidative metabolism of monocytes; and (ii) hista mine effectively enhances IFN-gamma production by preventing monocyte- induced oxidative damage to NK cells.