Besides its proinflammatory functions histamine released from basophils and mast cells during immediate-type hypersensitivity reactions is known to inhibit several lymphocyte functions like IL-2 and γ-IFN production. Recently, it has been shown that T helper cells of type 2 phenotype (T_H2) represent the T cell fraction which may play a pivotal role in the promotion of the allergic inflammatory eosinophilic late-phase reaction by secretion of cytokines, especially IL-4 and IL-5. We have investigated the effect of histamine on anti-CD3 induced IL-4 and IL-5 production by T_H2 cells. Histamine in concentrations between 10⁻⁷ and 10⁻⁵ mol/l concentration-dependently increased anti-CD3 induced IL-5 production up to 120%, whereas IL-4 production was not affected. The activity of histamine in increasing IL-5 production was mimicked by the H₂-receptor agonist dimaprit. Histamine induced increase in IL-5 production was inhibited by histamine H₂-receptor antagonists, but remained unaffected by H₁- or H₃-receptor antagonists. Administration of forskolin which directly stimulates the production of cAMP, the second messenger of the H₂-receptor, also resulted in an increase in anti-CD3 induced IL-5 production. These results indicate that the histamine-mediated increase in anti-CD3 induced IL-5 production is mediated via H₂-receptors. Consequently, histamine released from mast cells and basophils during the early-phase allergic reaction may act as an important stimulatory signal for the initiation of the allergic inflammatory late-phase reaction by increasing local IL-5 production of allergen triggered T_H2 cells.