MACROPHAGE-STIMULATING PROTEIN INHIBITS INDUCTION OF NITRIC-OXIDE PRODUCTION BY ENDOTOXIN-STIMULATED OR CYTOKINE-STIMULATED MOUSE MACROPHAGES

Human serum macrophage-stimulating protein (MSP) is a disulfide-linked heterodimer that induces motile and phagocytic activity of mouse resi dent peritoneal macrophages. In this work, we found that MSP blocked t he increase in macrophage nitric oxide synthase mRNA, as well as the a ssociated increase in nitric oxide production, that occurred in respon se to several stimuli. These included bacterial products and mammalian cytokines: endotoxin, and interferon-gamma plus endotoxin, interleuki n-2, or tumor necrosis factor-alpha. The inhibition by MSP of inductio n of nitric oxide synthase mRNA and; nitric oxide secretion was concen tration-dependent. The concentration of MSP that caused maximal inhibi tion of nitric oxide production was comparable with the optimum for st imulation of macrophage motile and phagocytic activity. Time course st udies showed that nitrate was first detected in culture fluid about 8 h after endotoxin stimulation, and it accumulated at a linear rate dur ing the ensuing 16 h. Inhibition by MSP occurred during the 8-h lipopo lysaccharide (LPS) induction period; inhibition was maximal when MSP a nd LPS were added together and decreased progressively to no inhibitio n as the interval between LPS and MSP addition increased to 11 h.