Autocrine regulation of macrophage proliferation by tumor necrosis factor-alpha.
We have examined production of tumor necrosis factor-alpha (TNF-alpha) from mouse bone marrow-derived macrophages (BMM) after stimulation by lipopolysaccharide (LPS), macrophage colony-stimulating factor (M-CSF/CSF-1), or granulocyte-macrophage colony-stimulating factor (GM-CSF). To control for effects of trace levels of LPS in culture media, we examined CSF-1 and GM-CSF-stimulated TNF-alpha production in relatively homogeneous populations of normal LPS-hyporesponsive C3H/HeJ BMM and a growth factor-dependent cell line (S1) of C3H/HeJ origin. We found that both TNF-alpha mRNA and protein are induced in these macrophage populations by CSF-1 stimulation alone. Stimulation with GM-CSF, however, appears to negatively regulate TNF-alpha protein levels. Most TNF-alpha detectable after CSF-1 or GM-CSF stimulation was cell associated. Only stimulation by LPS resulted in large amounts of released TNF-alpha detectable in culture supernatant. The hypothesis that endogenously produced TNF-alpha can function as an autocrine growth factor for CSF-1-stimulated proliferation was supported by the demonstration of a partial inhibition of BMM proliferation (p < 0.05) in the presence of a neutralizing anti-TNF-alpha antiserum. These results demonstrate that CSF-1 alone is capable of inducing expression of both TNF-alpha mRNA and protein, that GM-CSF may negatively regulate TNF-alpha protein production, and that endogenously produced TNF-alpha may provide additional growth signals for CSF-1 mediated BMM proliferation.
Branch
D R
DR
Canadian Red Cross Blood Transfusion Centre, Edmonton, Alberta, Canada.
Guilbert
L J
LJ
D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D006133:Growth Substances; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor