Induction of hepatocyte growth factor/scatter factor (HGF/SF) may be one of the critical steps in organ regeneration, wound healing, and embryogenesis. We previously reported the production of HGF/SF from various human leukemia cell lines and a high level of the growth factor in blood and bone marrow plasma from patients with various types of leukemia. We determined here the effects of hematopoietic cytokines on HGF/SF production in human leukemia cell lines, KG-1, a myeloid cell line, and RPMI-8226, a B cell line. Interferon (IFN)-g remarkably stimulated HGF/SF production in both cell lines at concentrations of more than 0.1 or 1 IU/ml. IFN-a and IFN-b were as effective as IFN-g in RPMI-8226 cells, but less than IFN-g in KG-1 cells. HGF/SF gene expression in KG-1 cells was also up-regulated by IFN-g. Granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-5 and IL-6 had no effect on HGF/SF production in the 2 leukemia cell lines. We also determined the effects of HGF/SF inducers known for human fibroblasts on the growth factor production in leukemia cells. Out of phorbol 12-myristate 13acetate (PMA), cholera toxin, IL-1b, and tumor necrosis factor (TNF)-a, the former three were as effective as IFN-g in KG-1 cells, but only TNF-a stimulated HGF/ SF production in RPMI-8226 cells, whose effect was less than those of IFN-a, IFN-b, and IFN-g. The effect of IFN-g in KG-1 cells was synergistic with that of PMA. In contrast with the effect in leukemia cells, HGF/SF induction by IFN-g in human skin fibroblasts was much less than that by PMA or cholera toxin. These results indicated that IFN-g is a potent inducer of HGF/SF in human leukemia cells. This finding suggests the presence of a homeostatic control mechanism in liver regeneration and repair: hepatic injury, DNA synthesis inhibition, or apoptosis caused by IFN-g is subsequently overcome by cytokine-induced HGF/ SF, a potent promoter of liver DNA synthesis.