Histamine receptors are expressed on neutrophils, and therefore, are likely to modulate neutrophil function. In this study, we investigated whether histamine modulates human neutrophil survival. Neutrophils were found to rapidly undergo spontaneous apoptosis upon culture in vitro and this was accelerated by high concentrations of histamine. Moreover, the percentage of apoptotic neutrophils was also markedly increased by treating with 10 mM histamine in the presence of inflammatory mediators, such as lipopolysaccharide (LPS), granulocyte macrophage-colony stimulating factor (GM-CSF), dibutyryl-cAMP (db-cAMP), or dexamethasone. Histamine-induced neutrophil apoptosis was inhibited by pyrilamine, a histamine receptor 1 antagonist, and by ranitidine, a selective histamine receptor 2 antagonist. In addition, diphenylene iodonium (DPI), an inhibitor of NADPH-oxidase, significantly blocked the apoptotic effect of histamine. Moreover, the induction of apoptosis by histamine was almost completely inhibited by zVAD-fmk, a pan-caspase inhibitor. In addition, immunoblotting showed that histamine induced the proteolytic activation of procaspase-3 in cell lysates treated with histamine. And, the protein kinase C (PKC)-delta inhibitor, rottlerin (5 microM) significantly blocked the apoptotic effect of histamine, though the cleavage of PKC-delta in 20 h cultured neutrophils was increased by histamine. However, an inhibitor of conventional PKC, Go6976 (100 nM) and a p38 mitogen-activated protein kinase inhibitor, SB203580 (10 microM), failed to block histamine-induced neutrophil apoptosis. These results suggest that high concentrations of histamine in local inflammatory and allergic lesions induce neutrophil apoptosis, and that this histamine-induced apoptosis is mediated by caspase activation and PKC-delta signaling.