title: Histaminergic regulation of interferon-gamma (IFN-gamma) production by human natural killer (NK) cells.
abstract: Monocytes, recovered from human peripheral blood by counter-current centrifugal elutriation, effectively inhibit the production of IFN-gamma by CD3-/56+ NK cells in response to IL-2. This study aimed at defining 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 of phagocytes, did not inhibit IFN-gamma production by NK cells. Further, catalase, a scavenger of hydrogen peroxide, completely reversed the inhibitory signal whereas scavengers of the superoxide anion, hypohalous acids, the hydroxyl radical, or nitric oxide synthesis inhibitors such as L-NMMA were ineffective. Inhibition of IFN-gamma production was operating on a pretranslational level, as indicated by the inability 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 enriched NK cells. Histamine, a biogenic amine which inhibits the generation of reactive oxygen metabolites in monocytes, abrogated the inhibition of IFN-gamma production in NK cells; by this mechanism, histamine strongly synergized with IL-2 to induce IFN-gamma in mixtures of NK cells and monocytes. The synergizing effect of histamine was specifically mediated by H2-type histamine receptors. We conclude that: (i) the induction of IFN-gamma mRNA in NK cells is effectively down-regulated by products of the oxidative metabolism of monocytes; and (ii) histamine effectively enhances IFN-gamma production by preventing monocyte-induced oxidative damage to NK cells.
authors.affiliation: Department of Virology, Ostra University Hospital, University of Göteborg, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Asea
authors.forename: M
authors.initials: M
authors.lastname: Hansson
authors.forename: C
authors.initials: C
authors.lastname: Czerkinsky
authors.forename: T
authors.initials: T
authors.lastname: Houze
authors.forename: S
authors.initials: S
authors.lastname: Hermodsson
authors.forename: O
authors.initials: O
authors.lastname: Strannegård
authors.forename: K
authors.initials: K
authors.lastname: Hellstrand
mesh_terms: D001483:Base Sequence; D002374:Catalase / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology
chemical_list: D006632:Histamine; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D002374:Catalase