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-1 beta. This study was undertaken to study the mechanisms leading to the IL-1 beta-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-1 beta 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-1 beta was blocked by cycloheximide, suggesting that de novo protein synthesis was required. Moreover, soluble IL-1 receptors inhibited the effect of IL-1 beta 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-1 beta-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-1 beta, 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-1 beta, IL-4, and IL-10 control the survival and differentiation of human monocytes through a regulation of autocrine M-CSF production.
Gruber
M F
MF
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
Williams
C C
CC
Gerrard
T L
TL
D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D016753:Interleukin-10; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D017493:Leukocyte Common Antigens