Sodium-butyrate-pretreated and Con A-stimulated P815 mast cell line generated 3T3 fibroblast proliferating activity. This fibroblast stimulatory activity was partially abrogated by three different substance P antagonists such as spantide (NK1 antagonist), FK224 (NK1 and NK2 antagonist) or FK888 (NK1 antagonist) or anti-substance P antibody. In addition to P815 mastocytoma cell, IL3-dependent, bone marrow-derived mast cells also generated fibroblast proliferating activity which was also partially abrogated by substance P antagonists. Anti-fibrogenic cytokine antibodies also inhibited mast cell-derived fibroblast proliferating activity. Substance P or histamine augmented fibrogenic cytokine-induced fibroblast proliferation which indicates that mast cell-derived histamine or substance P play an important role in induction of tissue fibrosis in fibrosing diseases.