1. Effect of 3M-003, an imidazoquinoline, on phagocyte candidacidal activity directly and via induction of peripheral blood mononuclear cell cytokines.
- Author
-
Brummer E, Antonysamy MA, Bythadka L, Gullikson GW, and Stevens DA
- Subjects
- Animals, Blood immunology, Candida physiology, Cytokines metabolism, Imidazoles pharmacology, Macrophages immunology, Mice, Mice, Inbred BALB C, Monocytes immunology, Neutrophils immunology, Candida immunology, Cytokines immunology, Immunologic Factors pharmacology, Leukocytes, Mononuclear immunology, Microbial Viability, Phagocytes immunology, Quinolines pharmacology
- Abstract
3M-003, like related imidazoquinoline immunomodulators, interacts with Toll-like receptor-7 (TLR-7) and TLR-8. TLRs are important in the defense against fungal pathogens. The effect of 3M-003 on killing of Candida was evaluated on mouse (BALB/c) effector cell lineages: monocytes, neutrophils, and macrophages. After direct application, 3M-003 (1-80 microg mL(-1)) enhanced (P<0.05-0.01) macrophage killing, comparable to killing by interferon-gamma-activated macrophages. 3M-003 did not directly enhance the candidacidal activity of monocytes or neutrophils. To test an effect mediated by leukocytes, BALB/c peripheral blood mononuclear cells (PBMC) were stimulated in vitro with 3M-003 to generate cytokine-containing supernatants. 3M-003 at 1 or 3 microM was optimal for the stimulation of PBMC to produce tumor necrosis factor-alpha and interleukin-12p40 in 24 h. For indirect tests, monolayers were treated with supernatants for 18 h, the supernatants were removed, and effector cells were tested; the supernatants enhanced (P<0.05-0.01) killing, in 2-4-h assays, by neutrophils from 42% to 73%, macrophages from 0% to 23%, and monocytes from 0% to 20%. 3M-003, presumably through TLRs, acts directly on macrophages to enhance fungal killing and stimulates PBMC to produce soluble factors that enhance killing by neutrophils, macrophages, and monocytes. 3M-003 could be a candidate for antifungal immunotherapy.
- Published
- 2010
- Full Text
- View/download PDF