A Cell‐to‐Cell Mediated Interaction Involving Monocytes and Non‐T/CD16+ Natural Killer (NK) Cells is Required for Histamine H2‐Receptor‐Mediated NK‐Cell Activation

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Abstract
Histamine (10-4 to 10-7 M) augmented natural killer cell cytotoxicity (NKCC) of human CD16+, non-T lymphocytes in vitro against the NK-sensitive target cells K562 erythroleukaemic, Molt-4 lymphoma, Chang liver cells and against Epstein-Barr virus (EBV)-transformed, NK-insensitive Daudi B-lymphoblastoid target cells by a mechanism of action involving a prostaglandin- and interleukin 1 (IL-1)-independent accessory function of monocytes. No evidence for the production of intermediary, NK-enhancing cytokines by histamine was obtained, indicating a cell-to-cell mediated interaction between monocytes and NK cells as a plausible mechanism of action for the NK-augmenting effect. Monocytes recovered by countercurrent centrifugal elutriation (CCE), but not monocytes recovered by adherence, reconstituted the effect of histamine when added to non-adherent NK cells. The development of NKCC in response to histamine was time-dependent with (i) an induction phase, dependent on the presence of accessory monocytes and ongoing histamine H2-receptor activation (half-maximal response required approximately 30 min treatment of large granular lymphocyte (LGL)-enriched lymphocytes and monocytes with histamine), and (ii) an effector phase, independent of the presence of monocytes or histamine receptor activation. Histamine-activated mononuclear cells (MNC) continued to exert augmented cytotoxicity for at least 8 h after removal of histamine and monocytes. In several experiments, histamine-activated NK-effector cells killed > 90% of the target cells at low baseline NKCC. We suggest that histamine may have a role in non-specific tumour defence by regulating an earlier unrecognized interplay between monocytes and NK cells.