Culture of macrophage-like P388D1 cells led to a spontaneous increase in release of interleukin-1 (IL-1). Addition of histamine enhanced the process as a function of its dose; histamine was effective at a concentration of as low as 10(-6)M and maximally at a dose of 10(-3)M. The effect of histamine was partially blocked by an H1-antagonist, diphenhydramine, at 10(-6)M - 10(-4)M. Ranitidine, an H2-antagonist, had no appreciable effect on the histamine-stimulated IL-1 release, even at a dose of 10(-5)M. At 10(-4)M it attenuated the histamine effect. Combination of the H1- and H2- antagonists resulted in a larger magnitude of attenuation of the histamine effect than that caused by either the H1-antagonist or the H2-antagonist alone. An H1-agonist, 2-pyridylethylamine, markedly augmented IL-1 release, reaching a maximum at 10(-4)M. Dimaprit, an H2-agonist, also stimulated IL-1 release, but the effect was far less than that of the H1 agonist. Dibutyryl adenosine 3':5'cyclic monophosphate (DBc-AMP) caused a marked rise in IL-1 production by the cells. The effects of DBc-AMP were synergistic to the effects of histamine at all doses examined. Histamine significantly augmented the uptake of 45Ca2+ by the cell as a function of time and dose of the amine. Addition of Co2+ attenuated the histamine effect at doses between 10(-5)M and 10(-4)M. These results suggest that the histamine-stimulated IL-1 release from P388D1 cells is dependent on both H1- and H2-receptors and involves both influx of calcium ions to the cells and altered intracellular concentration of adenosine 3':5'cyclic monophosphate.