Infiltrating polymorphonuclear leukocytes (PMN) in the peritoneal cavity were found to express L-histidine decarboxylase (HDC), the rate-limiting enzyme of histamine synthesis, in a csein-induced peritonitis model. Expression of HDC was detected in the elicited PMN, but not in the peripheral blood leukocytes. The peritoneal lavage fluids in this model were found to augment histamine synthesis in PMN isolated from the bone marrow. Rapid post-translational processing of HDC was observed in PMN, and the dominant form of HDC was the mature 53-kDa form, which was found to co-localize with a granule enzyme, matrix metalloproteinase-9 (MMP-9). Treatment of PMN with the phorbol ester PMA, which stimulates the release of MMP-9, did not liberate the granular HDC. Immunofluorescence studies using an anti-HDC antibody strongly suggested that HDC is bound to the cytosolic side of the granule membranes. These observations suggest that HDC is induced upon infiltration of PMN into the mouse peritoneal cavity and that histamine is synthesized by HDC attached to the granule membranes of PMN.