Effect of 3M-003, an imidazoquinoline, on phagocyte candidacidal activity directly and via induction of peripheral blood mononuclear cell cytokines

• Published in: FEMS immunology and medical microbiology Vol. 59; no. 1; pp. 81 - 89
• Main Authors: Brummer, Elmer, Antonysamy, Mary A., Bythadka, Lakshmi, Gullikson, Gary W., Stevens, David A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2010; Blackwell; Oxford University Press
• Subjects: Animals; antifungal activity; Biological and medical sciences; Blood; Blood - immunology; Candida; Candida - immunology; Candida - physiology; Cytokines; Cytokines - immunology; Cytokines - secretion; Effector cells; Fundamental and applied biological sciences. Psychology; Fungi; Fungicides; Imidazoles - pharmacology; imidazoquinoline; Immune system; Immunologic Factors - pharmacology; Immunomodulation; immunomodulator; Immunomodulators; Immunotherapy; Interferon; Interleukins; Leukocytes; Leukocytes (mononuclear); Leukocytes (neutrophilic); Leukocytes, Mononuclear - immunology; Macrophages; Macrophages - immunology; Mice; Mice, Inbred BALB C; Microbial Viability; Microbiology; Monocytes; Monocytes - immunology; Neutrophils; Neutrophils - immunology; Peripheral blood mononuclear cells; phagocytes; Phagocytes - immunology; Proteins; Quinolines - pharmacology; Toll-like receptors; Tumor necrosis factor-α; γ-Interferon; immunomodulator; cytokines; phagocytes; antifungal activity; imidazoquinoline; Immunomodulator; antifungal activity imidazoquinoline; Antifungal agent; Blood cell; Immunology; Mononuclear cell; Peripheral blood circulation; Cytokine; Phagocyte
• ISSN: 0928-8244; 1574-695X; 2049-632X
• DOI: 10.1111/j.1574-695X.2010.00664.x

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 µg mL−1) enhanced (P<0.05–0.01) macrophage killing, comparable to killing by interferon-γ-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 µM was optimal for the stimulation of PBMC to produce tumor necrosis factor-α 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.