Histamine inhibits neutrophil NADPH oxidase activity triggered by the lipoxin A4 receptor-specific peptide agonist Trp-Lys-Tyr-Met-Val-Met

• 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 A4 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 H2-type histamine receptors (H2R), 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.

Keyword

Chemotactic Factors/immunology/pharmacology

Cytoplasmic Granules/drug effects/immunology

Down-Regulation

Enzyme Inhibitors/immunology/pharmacology

Histamine/immunology/*pharmacology

Humans

N-Formylmethionine Leucyl-Phenylalanine/immunology/pharmacology

NADPH Oxidase/*antagonists & inhibitors/immunology

Neutrophils/drug effects/*enzymology/immunology

Oligopeptides/immunology/*pharmacology

Receptors

Cell Surface/*agonists/immunology

*Receptors

Formyl Peptide

*Receptors

Lipoxin

Research Support

Non-U.S. Gov't

Signal Transduction/drug effects

Superoxides/immunology/*metabolism

Tetradecanoylphorbol Acetate/immunology/pharmacology

Publication and Content Type

ref (subject category)

art (subject category)