The heparin-binding group II subfamily of secretory phospholipase A(2)s (sPLA(2)s), such as sPLA(2)-IIA and -IID, augments stimulus-induced arachidonic acid (AA) release through the cellular heparan sulfate proteoglycan (HSPG)-dependent pathway when transfected into HEK293 cells. Here we show that the closest homolog, sPLA(2)-IIE, also promotes stimulus-induced AA release and prostaglandin (PG) production similar to those elicited by HSPG-dependent sPLA(2)s. Confocal laser microscopic analysis demonstrates the location of sPLA(2)-IIE in cytoplasmic punctate compartments. sPLA(2)-IIE also enhances leukotriene (LT) production and granule exocytosis by RBL-2H3 mastocytoma cells. Expression of sPLA(2)-IIE was highly upregulated in mice injected with lipopolysaccharide (LPS) and in mice with experimental atopic dermatitis. These observations suggest that this enzyme plays a role in the inflammatory process, as proposed for other group II subfamily sPLA(2)s.