Human granulocyte-monocyte colony-stimulating factor and interleukin 3 stimulate monocyte cytotoxicity through a tumor necrosis factor-dependent mechanism.
Human colony-stimulating factors (CSF) exert multiple effects on the proliferation, differentiation, and function of myeloid lineage cells. In this study, the effects of three recombinant human CSFs (granulocyte-monocyte CSF [GM-CSF], interleukin 3 [IL-3], and granulocyte CSF [G-CSF]) on antibody-independent monocyte tumoricidal activity were investigated by using WEHI 164 fibrosarcoma cells as monocyte-sensitive targets. None of the CSFs directly induced monocyte cytotoxicity, although both GM-CSF and IL-3 were found to significantly enhance monocyte killing in response to a second stimulatory event (endotoxin). No effect was seen with G-CSF. Antitumor necrosis factor antibody completely abolished CSF-enhanced monocyte cytotoxicity, which suggests that this effect was mediated through increased release of tumor necrosis factor (TNF). As previously shown for GM-CSF, IL-3 was found to induce cytoplasmic accumulation of TNF messenger RNA (mRNA) after 18 hours of exposure. These results suggest that GM-CSF and IL-3 may stimulate monocyte killing indirectly by enhancing expression of TNF mRNA, thereby leading to augmented TNF protein secretion in response to a second activation signal.
Cannistra
S A
SA
Division of Tumor Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
Vellenga
E
E
Groshek
P
P
Rambaldi
A
A
Griffin
J D
JD
D001696:Biomechanical Phenomena; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D003115:Colony-Stimulating Factors; D004731:Endotoxins; D006133:Growth Substances; D007377:Interleukin-3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor