Synergistic stimulation of macrophage proliferation by the monokines tumor necrosis factor-alpha and colony-stimulating factor 1.
The effects of pure recombinant human tumor necrosis factor-alpha (TNF) on the CSF-1-stimulated proliferation of well-defined populations of murine macrophages are examined. Primary bone marrow-derived macrophages (BMM) from endotoxin-resistant C3H/HeJ mice were characterized for homogeneity in comparison with a cloned, growth factor-dependent macrophage cell line (S1) also derived from C3H/HeJ bone marrow cells. The mitogenic effects of each factor, alone and in combination, on the proliferation of both macrophage populations over a two-day culture period were studied. In contrast to CSF-1, TNF alone only slightly stimulated macrophage proliferation. However, the combination of CSF-1 and TNF stimulated proliferation of both primary BMM and S1 cells 1.5- to 2-fold greater than the sum of their predicted individual contributions. Such synergy was observed even at very high (plateau) levels of factors. TNF was found to transiently down-regulate CSF-1 receptor levels on both populations. Down-regulation was maximal at one hour; however, receptor numbers returned to initial, or greater, levels after 24 hours of incubation. Thus, TNF, an inducible monokine, greatly enhances the maximal mitogenic effects of CSF-1, an inducer of TNF production. These observations suggest an autocrine rule for TNF that involves synergy with (and perhaps obligatory cooperation with) CSF-1 in the regulation of macrophage proliferation.
Branch
D R
DR
Department of Immunology, University of Alberta, Edmonton, Canada.
Turner
A R
AR
Guilbert
L J
LJ
D000818:Animals; D001853:Bone Marrow; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003115:Colony-Stimulating Factors / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D011956:Receptors, Cell Surface; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor