Cytokine enhancement of complement-dependent phagocytosis by macrophages: synergy of tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor for phagocytosis of Cryptococcus neoformans.
We have examined the regulation of complement dependent phagocytosis by macrophage-activating cytokines. Tumor necrosis factor (TNF)-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not interferon-gamma, interleukin-4 or macrophage-CSF, stimulated ingestion of the encapsulated fungal pathogen Cryptococcus neoformans by resident peritoneal macrophages in vitro. This was dependent upon opsonization of the yeasts with complement, 72 h of incubation with the cytokines for maximum effect, and the obligate involvement of the macrophage CR3 receptor. TNF-alpha and GM-CSF synergized at low concentrations, resulting in dramatic up-regulation of phagocytosis when compared to either cytokine alone. Supernatants from C. neoformans-specific T cells also increased macrophage phagocytic efficiency. Finally, the administration of neutralizing mAb specific for TNF-alpha and GM-CSF increased mortality in C. neoformans-infected mice, and induced the rapid progression of disease with involvement of the brain and meninges. We conclude that TNF-alpha and GM-CSF are potent regulators of complement-dependent phagocytosis by murine macrophages. Macrophage activation with these two cytokines can completely overcome the anti-phagocytic properties of the virulent yeasts. Our results, therefore, implicate TNF-alpha and GM-CSF as important mediators of resistance to encapsulated pathogens such as C. neoformans where ingestion of the organism is a critical process in host resistance.
Collins
H L
HL
Department of Clinical Sciences, London School of Hygiene and Tropical Medicine, GB.
Bancroft
G J
GJ
D000818:Animals; D000911:Antibodies, Monoclonal; D003453:Cryptococcosis / Q000276:immunology; D003455:Cryptococcus neoformans / Q000276:immunology*; D016207:Cytokines / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005260:Female; D005856:Germ-Free Life; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D010587:Phagocytosis / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D016207:Cytokines; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor