Histamine is a potent inducer of IL-18 and IFN-gamma in human peripheral blood mononuclear cells

Histamine (10(-7) to 10(-4) M) concentration-dependently stimulated the pro duction of IL-18 and IFN-gamma and inhibited the production of IL-2 and IL- 10 in human PBMCs, Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of h istamine on cytokine production were all antagonized by H-2 receptor antago nists ranitidine and famotidine in a concentration-dependent manner, but no t by H-1 and H-3 receptor antagonists. Selective H-2 receptor agonists, 4-m ethylhistamine and dimaprit, mimicked the effects of histamine on five kind s of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 mu M, respe ctively. These findings indicated that histamine caused cytokine responses through the stimulation of H-2 receptors, All effects of histamine on cytok ine responses were also abolished by the presence of either anti-IL-18 Ab o r IL-1 beta-converting enzyme/caspase-1 inhibitor, indicating that the hist amine action is dependent on mature IL-18 secretion and that IL-18 producti on is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependentl y stimulated IL-12 and IFN-gamma production and inhibited the IL-2 and IL-1 0 production, IFN-gamma production induced by IL-18 was inhibited by anti-I L-12 Ab, showing the marked contrast of the effect of histamine. Thus hista mine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18 initiating cytokine cascade without ind ucing IL-12 production.