Since a wide variety of heterogeneity was found in tissue mast cells, recent studies have focused on the process of differentiation and maturation of mast cells. It has been largely accepted that the ability of histamine synthesis is high in the mucosal type mast cells whereas that is low in the tissue-connective type mast cells, although it remains largely unknown how histamine synthesis is regulated during differentiation. Interleukin (IL)-4 is one of the candidate factors that regulate the process of mast cell differentiation. We investigated the effects of IL-4 on histamine synthesis using a murine IL-3-dependent mucosal-type mast cell line, BNu-2cl3. IL-4 drastically suppressed histamine synthesis at the transcriptional levels. Storage of histamine was significantly decreased upon prolonged treatment with IL-4. Down-regulation in expression of histidine decarboxylase by IL-4 was restored by addition of excessive amount of IL-3. Changes in mRNA expression of mouse mast cell proteases (MMCPs) in the cells treated with IL-4 mimicked the differentiation process from mucosal-type to connective tissue-type mast cells; mRNA expression of MMCP2 was decreased, whereas that of MMCP4 and carboxypeptidase A3 were unchanged. These results suggest that IL-4 should play a critical role in suppression of histamine synthesis in mucosal-type mast cells.