EFFECT OF AMINOPEPTIDASE INHIBITORS ON THE PRODUCTION OF VARIOUS CYTOKINES BY PERIPHERAL-BLOOD MONONUCLEAR-CELLS AND STROMAL CELLS AND ON STEM-CELL FACTOR GENE-EXPRESSION IN STROMAL CELLS - COMPARISON OF UBENIMEX WITH ITS STEREOISOMERS

The effects of three aminopeptidase (AP) inhibitors on the production of various kinds of cytokines from normal human peripheral blood monon uclear cells (PB-MNC) and a human clonal stromal cell line, KM-102, ha ve been studied in vitro. Ubenimex stimulated the production of G-CSF, GM-CSF, IL-6, IFN-gamma and TNF-alpha by PB-MNC, that of GM-CSF from stromal cells, and enhanced the expression of stem cell factor mRNA in stromal cells. These results suggest that ubenimex exerts its stimula tory effect on haematopoiesis through stimulation of the production of various haematopoietic growth factors from PB-MNC and stromal cells, and its inhibitory effect on haematopoiesis and tumour growth through stimulation of the production of IFN-gamma and TNF-alpha. Two stereois omers of ubenimex, (2S,3S)-AHPA-(R)-Leu and (2R,3S)-AHPA-(R)-Leu, exer ted little or no such effects, indicating that the stimulatory effects of ubenimex on cytokine production are exerted through inhibition of leucine AP, AP-N, or both, but not of AP-B, which is present on the ce ll surface.