Histamine releasing factors (HRFs) have been demonstrated to be secreted by human lymphocytes and monocytes (alveolar macrophages); however, none has been purified to date. Because of the similarity of our HRF to the physical chemical properties of interleukin-1 (IL-1) and tumor necrosis factor (TNF), we have assessed the ability of preparations of IL-1 and TNF to cause basophil histamine release (HR). Human recombinant pro-IL-1 beta, recombinant mature IL-1, and, to a lesser extent, human recombinant TNF caused significant HR from a subpopulation of donor basophils. The pro-IL-1 beta elicited a dose response between 40 and 800 ng/ml; higher concentrations were inhibitory. Approximately 30% of subjects tested are responsive to either mature IL-1 or TNF. These share the same responder subset, but the magnitude of the TNF response is considerably less. A response to the pro-IL-1 was restricted to those subjects with prominent HR to anti-IgE; the response to mature IL-1 and TNF was unrelated to the response to anti-IgE. As in other functional assays, the pro-IL-1 is 50- to 100-fold less potent than mature IL-1, and unlike human HRF, it is highly unstable and rapidly loses activity. Mononuclear cell-derived HRF differs in physicochemical properties from IL-1 or TNF; nevertheless, it appears likely that a variety of cytokines may possess histamine-releasing capability.