title: Macrophage colony-stimulating factor (M-CSF) induction of enhanced anticryptococcal activity in human monocyte-derived macrophages: synergy with fluconazole for killing.
abstract: Induction of enhanced anticryptococcal activity in human monocyte-derived macrophages (HMM) by macrophage colony-stimulating factor (M-CSF) and possible synergy with fluconazole (FCZ) for killing of Cryptococcus neoformans (CN) was studied. Fungistasis by HMM cultured in medium for 3, 5, or 7 days was minimal, 0-17%. The fungistasis of HMM cocultured with M-CSF at 1000, 5000, or 20,000 U/ml for 3, 5, or 7 days was increased significantly (P < 0.02) at all study times and by all concentrations. The optimal M-CSF concentration for HMM treatment for enhanced fungistasis was 5000 U/ml for Day 3 (84%), whereas 1000 U/ml was sufficient with more prolonged HMM culture and M-CSF treatment (Days 5-7). The enhancement by M-CSF was seen with four different donors and three patient isolates of CN. FCZ at 5 micrograms/ml was fungicidal, 28 +/- 17% (n = 8). Killing by FCZ was enhanced by HMM treated with M-CSF 5000 or 20,000 U/ml for 5 days compared to control HMM, 58% (P = 0.001) and 60% (P = 0.002) vs 48%, respectively. This was also seen with HMM cultured with 1000 U/ml M-CSF for 7 days (P < 0.05). M-CSF also induced in HMM enhancement of fungistasis by lower, fungistatic, concentrations of FCZ. These results demonstrate enhancement of anticryptococcal activity by HMM treated with M-CSF and synergy with FCZ for inhibition and killing. These findings may provide a rationale for combined treatment of FCZ and M-CSF against cryptococcosis.
authors.affiliation: Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128-2699, USA.
authors.forename: F
authors.initials: F
authors.lastname: Nassar
authors.forename: E
authors.initials: E
authors.lastname: Brummer
authors.forename: D A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D002478:Cells, Cultured; D003453:Cryptococcosis / Q000517:prevention & control; D003454:Cryptococcus / Q000276:immunology*; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology*; D013997:Time Factors
chemical_list: D015725:Fluconazole; D016186:Receptor, Macrophage Colony-Stimulating Factor