MACROPHAGE-COLONY-STIMULATING FACTOR EXPRESSION BY ANTI-CD45 STIMULATED HUMAN MONOCYTES IS TRANSCRIPTIONALLY UP-REGULATED BY IL-1-BETA AND INHIBITED BY IL-4 AND IL-10

Macrophage (M)-CSF is a survival and differentiation factor for mononuclear phagocytes. Stimulation of human monocytes with immobilized mAb directed to CD45 induces M-CSF message and small amounts of protein, which is strongly augmented by costimulation with IL-1beta. This study was undertaken to study the mechanisms leading to the IL-1beta-induced up-regulation of M-CSF production and to determine how the antiinflammatory cytokines, IL-4 and IL-10, affect M-CSF production in this system. We demonstrate that IL-1beta enhanced M-CSF mRNA levels, in part, by increasing M-CSF gene transcription but had no effect on M-CSF message half-life. The enhancement of M-CSF message levels in the presence of IL-1beta was blocked by cycloheximide, suggesting that de novo protein synthesis was required. Moreover, soluble IL-1 receptors inhibited the effect of IL-1beta on M-CSF production thus confirming that these effects were IL-1 receptor mediated. Both IL-4 and IL-10 strongly inhibited M-CSF secretion by anti-CD45/IL-1beta-induced monocytes that was accompanied by decreased M-CSF message levels. IL-4 and IL-10 repressed M-CSF gene transcription but did not affect M-CSF message half-life. These findings demonstrate that IL-1beta, at least in part, transcriptionally up-regulates M-CSF production in anti-CD45-stimulated human monocytes, a process that can be negatively regulated by both IL-4 and IL-10. These results suggest that IL-1beta, IL-4, and IL-10 control the survival and differentiation of human monocytes through a regulation of autocrine M-CSF production.