Interleukin-2 (IL-2) inhibited histamine release from rat mast cells induced by compound 48/80 in a concentration-dependent manner. The inhibitory effect of IL-2 on histamine release was also dependent on the length of the incubation period; the maximum inhibition was achieved at 8 h after IL-2 addition. Furthermore, IL-2 inhibited not only IP3 production but also 45Ca uptake in mast cells stimulated by compound 48/80. Since IL-2 enhanced [3H]-leucine uptake into mast cells, this suggests that protein synthesis may be related in some way with the inhibition of histamine release. IL-2 treatment augmented the synthesis of a protein having a molecular weight of approximately 35 kDa. From Western blotting analysis, it became clear that the production of lipocortin-I was augmented in rat mast cells by IL-2 treatment. The present study shows that IL-2 induces the synthesis of lipocortin-I in mast cells and that lipocortin-I may play some role in inhibiting histamine release from mast cells.