In the air pouch-type allergic inflammation model in rats, histamine produced in the late phase plays a role in downregulation of leukocyte infiltration into the pouch fluid. In the pouch fluid, we found two kinds of histamine production-increasing factor (HPIF); HPIF-1, which induces histamine production in bone marrow cells, and HPIF-2, which enhances the activity of HPIF-1. Isoelectric point and molecular weight of HPIF-1 and HPIF-2 were estimated to be pI 4-5 and 25-40 kD, and pI 7-8 and about 100 kD, respectively. The histamine-producing ability of bone marrow cells increased after the antigen challenge, but that of peripheral leukocytes decreased markedly 8 h after the antigen challenge. Pharmacological analysis indicated that HPIF-1 induces histamine production through activation of protein kinase C and tyrosine kinase. Differentiation of bone marrow cells to histamine-producing cells by HPIF-1 was also indicated. From these observations, the histamine production in the late phase of allergic inflammation is suggested to be regulated by the production of HPIF-1, proliferation/differentiation of histamine-producing cells, and infiltration of histamine-producing cells in blood circulation into the inflammatory site.