Lipopolysaccharide (LPS) is an inducer of interleukin (IL)-18, which in turn plays important roles in immune responses. Previously, we reported that tumor necrosis factor (TNF)-alpha production could be detected in human peripheral blood mononuclear cells (PBMCs) treated with relatively low concentration of LPS (1 ng/ml), but that same concentration of LPS could not induce IL-18 production. In the present study, we found that LPS at relatively high concentrations (10-1000 ng/ml) induced IL-18 production in a concentration-dependent manner both in monocytes isolated from PBMC, and that histamine (10(-7) to 10(-4) M) inhibited IL-18 production induced by LPS. The studies using receptor subtype-selective agonists and antagonists suggested that the effect of histamine was mediated by H2 receptor but not by H1, H3 and H4 receptors. Therefore, the stimulation of H2 receptor might be beneficial in the treatment of sepsis through inhibiting LPS-elicited IL-18.