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Abstract The vasoactive amine histamine is found at high concentrations in the immune and inflammatory tissues. Earlier studies have revealed that histamine regulates the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent formation of oxygen radicals by phagocytic cells. However, the effects of histamine on intracellular signal transduction mechanisms of relevance to oxidase regulation remain controversial. For this study, we investigated the effects of histamine on NADPH oxidase activity in human neutrophil granulocytes triggered by a lipoxin A[sub 4] receptor agonist [the hexapeptide Trp-Lys-Tyr-Met-Val-Met (WKYMVM), a formyl peptide receptor (FPR) agonist (the chemotactic tripeptide formylmethionyl-leucyl-phenylalanine (fMLF)) and an activator of protein kinase C (phorbol myristate acetate (PMA)]. We report that histamine, acting via H[sub 2] -type histamine receptors (H[sub 2] R), suppresses NADPH oxidase-dependent formation of oxygen radicals induced by WKYMVM and fMLF but not that induced by PMA. Peptide-induced mobilization of granule-localized complement receptor 3 (CR3) was unaffected by histamine suggesting that the inhibition specifically affected NADPH oxidase activation. Our data suggest that histamine downregulates FPRL1- and FPR-induced NADPH oxidase activity upstream of protein kinase C (PKC) and downstream of the separation of the peptide-induced signal into granule secretion and oxidase activation. [ABSTRACT FROM AUTHOR]

Autologous monocytes irreversibly suppressed Functions of human natural killer (NK) cells including baseline and lymphokine-induced cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC). and interleukin-2 (IL-2)-induced proliferation. The suppression of these NK-cell functions was cell contact-dependent and could be evoked only by purified monocytes, recovered directly from peripheral blood by countercurrent centrifugal elutriation (CCE). The presence of monocytes also induced the disappearance of CD16 and CD56 antigen on CD3 NK cells (CD3 :16+/56+→CD3 /16+ /56 ). By contrast. T-cell proliferation and the expression of CD3 on CD56 T cells were not susceptible to cell contact-mediated suppression by monocytes. The biogenic amine serotonin abrogated monocyte-induced suppression of NK-cell functions as well as down-modulation of CD16;56 NK-cell antigen. Serotonin thus markedly augmented baseline and lymphokine-induced NK-cell cytotoxicity. ADCC. and NK-cell proliferation. and maintained the expression of NK-cell surface antigens in the presence of elutriated monocytes. The effect of serotonin was mediated by 5-HT1A-type serotonin receptors (5-HT1AR) as indicated by mimicry exerted by 5-HT1AR agonists such as 8-OH-DPAT and (+)-ALK. partial antagonism by the 5-HT1AR antagonists pindolol and cyproheptadine. and lack of antagonism by the 5-HT2R antagonist ketanserin or the 5-HT3 R antagonist ondansetron. Our data are suggestive of a cell-to-cell-mediated mechanism by which monocytes down-modulate NK-cell function and phenotype and its serotonergie regulation. [ABSTRACT FROM AUTHOR]

Human peripheral blood monocytes, recovered by counter-current centrifugal elutriation, suppressed interleukin-2 (IL-2)-induced proliferation of autologous lymphocytes, recovered from low density Percoll fractions. Cell sorting experiments, analysis of phenotype of proliferating cells, and removal of defined cellular subsets by complement cytotoxicity revealed that IL-2-induced proliferation was confined to CD3-/16+/56+ natural killer (NK) cells, Monocyte-induced suppression of NK-cell proliferation was completed within 1 h of incubation with monocytes and unrelated lo the formation of prostaglandins or other intermediary factors. The biogenic amine histamine. acting via H2-type histamine receptors (H2R) on monocytes, completely counteracted the monocyte-mediated suppression of IL-2-induced NK-cell proliferation. Our data are suggestive of a H2R-regulated, cell-cell-mediated mechanism by which monocytes down-modulate NK-cell proliferation. [ABSTRACT FROM AUTHOR]

Histamine (10-4to 10-7 M) augmented natural killer cell cytotoxicity (NKCC)of human CD16+. non-T lymphocytes In vitro against the NK-sensitive target cells K562erythroleukaemic. Molt-4 lymphoma, Chang liver cells and against Epstein Barr virus (EBV)-transformed, NK-insensitive Daudi B-lymphoblastoid target ceils by a mechanism of action involving a prostaglandin- and interleukin 1 (IL-l)-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. [ABSTRACT FROM AUTHOR]