title: Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2.
abstract: Interleukin-2 (IL-2) is recognized as a major activating signal for human natural killer (NK) cells. The presence of monocytes alters NK cell responsiveness to IL-2. Thus, while IL-2 effectively augments NK cell cytotoxicity (NKCC) in monocyte-depleted NK effector cells, it is relatively ineffective or even suppressive for NK cells in monocyte-containing, NK-cell-enriched mononuclear cell fractions. Here we report that concomitant treatment with IL-2 and the biogenic amine histamine synergistically augmented NKCC against K562 and Daudi target cells of CD3-/CD16+ human NK cells in the presence but not in the absence of monocytes. Addition of peripheral-blood monocytes, recovered by countercurrent centrifugal elutriation, to purified NK cells abrogated IL-2 induced NK cell activation, reconstituted the synergistic, NK-activating effects of histamine and IL-2, and strongly reduced baseline NKCC. The effects of histamine on baseline NKCC and on NK cell responsiveness to IL-2 were related to counteraction of monocyte-mediated NK cell suppression. By contrast, histamine did not affect baseline or IL-2-induced NKCC in mixtures of NK cells and monocytes when the latter cells were recovered after adherence. The effect of histamine on NK cell responsiveness to IL-2 was mediated by H2-type histamine receptors, as judged by mimicry exerted by the specific H2 receptor agonist dimaprit, but not by an H2-receptor-inactive derivative of this compound, N-methyldimaprit, and blocking by the H2 receptor antagonist ranitidine. Experiments in which monocytes and nonadherent NK cells were separately pretreated with ranitidine prior to histamine treatment suggested that NK-regulatory effects of histamine were mediated by H2 receptors on monocytes. Our data suggest that histamine may provide an important signal in the regulation of NK cell responsiveness to IL-2.
authors: Department of Clinical Virology, University of Göteborg, Sweden.
authors: K
authors: K
authors: Hellstrand
authors: S
authors: S
authors: Hermodsson
mesh_terms: D000943:Antigens, Differentiation / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000502:physiology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D011961:Receptors, Fc / Q000032:analysis; D011970:Receptors, Histamine H2 / Q000032:analysis / Q000502:physiology; D017452:Receptors, IgG
chemical_list: D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011961:Receptors, Fc; D011970:Receptors, Histamine H2; D017452:Receptors, IgG; D006632:Histamine; D007371:Interferon-gamma