Macrophage activation by granulocyte/macrophage colony-stimulating factor. Priming for enhanced release of tumor necrosis factor-alpha and prostaglandin E2.
The macrophage-activating properties of murine recombinant granulocyte-macrophage (GM)-CSF were studied in murine peritoneal macrophages with respect to metabolism, endocytosis, PGE2 and TNF-alpha release, and tumor cytotoxicity. GM-CSF was found to be a potent stimulus for RNA and protein synthesis, glucose consumption, pinocytosis, and FcR-independent phagocytosis. Macrophages were activated by GM-CSF to kill TNF-alpha-insensitive Eb lymphoma cells but failed to generate cytotoxicity against TNF-alpha-sensitive L929 cells. Although GM-CSF alone was incapable of stimulating TNF-alpha release, it primed macrophages for elevated TNF-alpha production in response to IFN-gamma plus LPS. The priming effect of GM-CSF disappeared upon longer incubation (greater than 12 h) and was followed by a strongly reduced responsiveness to stimuli that release TNF-alpha. Late-stage suppression could be reverted by treatment with the cyclooxygenase blocker indomethacin, and GM-CSF-induced priming for enhanced TNF-alpha release was entirely restored. The responsible arachidonic acid product mediating suppression was found to be PGE2, because 1) GM-CSF-primed macrophages released enhanced amounts of PGE2 and 2) indomethacin-restored macrophages were again suppressed when exogenous PGE2 was added back in amounts produced by GM-CSF-primed macrophages. Although GM-CSF potently induced TNF-alpha gene transcription by 20 h of treatment, PGE2 interfered with translation into the secreted TNF-alpha protein. These data show that GM-CSF is capable of priming for the enhanced release of two factors, initially for TNF-alpha and subsequently for PGE2. The temporally delayed generation of these two mediators suggests an autoregulatory circuit in which the later produced PGE2 limits GM-CSF-induced macrophage activation.
Heidenreich
S
S
Institute of Immunology, University of Marburg, West Germany.
Gong
J H
JH
Schmidt
A
A
Nain
M
M
Gemsa
D
D
D000818:Animals; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism* / Q000502:physiology; D004705:Endocytosis; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000502:physiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005947:Glucose; D015232:Dinoprostone