INDUCTION OF HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR BY INTERFERON-GAMMA IN HUMAN LEUKEMIA-CELLS

Induction of hepatocyte growth factor/scatter factor (HGF/SF) may be o ne of the critical steps in organ regeneration, wound healing,and embr yogenesis. We previously reported the production of HGF/SF from variou s human leukemia cell lines and a high level of the growth factor in b lood and bone marrow plasma from patients with various types of leukem ia. We determined here the effects of hematopoietic cytokines on HGF/S F production in human leukemia cell lines, KG-1, a myeloid cell line, and RPMI-8226, a B cell line. Interferon (IFN)-gamma remarkably stimul ated HGF/SF production in both cell lines at concentrations of more th an 0.1 or 1 IU/ml. IFN-alpha and IFN-beta were as effective as IFN-gam ma in RPMI-8226 cells, but less than IFN-gamma in KG-1 cells. HGF/SF g ene expression in KG-1 cells was also up-regulated by IFN-gamma. Granu locyte colony-stimulating factor (G-CSF), granulocyte/macrophage colon y-stimulating factor (GM-CSF), interleukin (IL)-5 and IL-6 had no effe ct on HGF/SF production in the 2 leukemia cell lines. We also determin ed the effects of HGF/SF inducers known for human fibroblasts on the g rowth factor production in leukemia cells. Out of phorbol 12-myristate 13-acetate (PMA), cholera toxin, IL-1 beta, and tumor necrosis factor (TNF)-alpha, the former three were as effective as IFN-gamma in KG-1 cells, but only TNF-alpha stimulated HGF/SF production in RPMI-8226 ce lls, whose effect was less than those of IFN-alpha, IFN-beta, and IFN- gamma. The effect of IFN-gamma in KG-1 cells was synergistic with that of PMA. In contrast with the effect in leukemia cells, HGF/SF inducti on by IFN-gamma in human skin fibroblasts was much less than that by P MA or cholera toxin. These results indicated that IFN-gamma is a poten t 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-gamma is subsequently overcome by cytokine-induced HGF/SF, a p otent promoter of liver DNA synthesis. (C) 1998 Wiley-Liss, Inc.