Polyene macrolide antifungal drugs trigger interleukin-1β secretion by activating the NLRP3 inflammasome

• Published in: PloS one 2011, Vol.6 (5), p.e19588-e19588
• Main Authors: Darisipudi, Murthy Narayana, Allam, Ramanjaneyulu, Rupanagudi, Khader Valli, Anders, Hans-Joachim
• Format: Article
• Language: English
• Subjects: Activation; Amphotericin B; Amphotericin B - pharmacology; Animals; Antibiotics; Antifungal agents; Antifungal Agents - pharmacology; Apoptosis Regulatory Proteins; Biology; Bone marrow; CARD Signaling Adaptor Proteins; Carrier Proteins - metabolism; Caspase; Caspase 1 - metabolism; Caspase-1; Cell culture; Cytokines; Cytoskeletal Proteins - metabolism; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Drugs; Efflux; Fungal infections; Fungi; Fungicides; IL-1β; Immunity; Immunity, Innate; Immunoblotting; Inflammasomes; Inflammasomes - drug effects; Innate immunity; Interleukin; Interleukin-1beta - secretion; Interleukins; Macrolides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Natamycin; Natamycin - pharmacology; NLR Family, Pyrin Domain-Containing 3 Protein; Nystatin; Nystatin - pharmacology; Oxidative stress; Pathogenesis; Pattern recognition; Phagocytosis; Phagocytosis - drug effects; Potassium; Potassium - metabolism; Signal Transduction; Toll-Like Receptors; Toxins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019588

The use of antimycotic drugs in fungal infections is based on the concept that they suppress fungal growth by a direct killing effect. However, amphotericin and nystatin have been reported to also trigger interleukin-1β (IL-1β) secretion in monocytes but the molecular mechanism is unknown. Here we report that only the polyene macrolides amphotericin B, nystatin, and natamycin but none of the tested azole antimycotic drugs induce significant IL-1β secretion in-vitro in dendritic cells isolated from C57BL/6 mouse bone marrow. IL-1β release depended on Toll-like receptor-mediated induction of pro-IL-1β as well as the NLRP3 inflammasome, its adaptor ASC, and caspase-1 for enzymatic cleavage of pro-IL-1β into its mature form. All three drugs induced potassium efflux from the cells as a known mechanism for NLRP3 activation but the P2X7 receptor was not required for this process. Natamycin-induced IL-1β secretion also involved phagocytosis, as cathepsin activation as described for crystal-induced IL-1β release. Together, the polyene macrolides amphotericin B, nystatin, and natamycin trigger IL-1β secretion by causing potassium efflux from which activates the NLRP3-ASC-caspase-1. We conclude that beyond their effects on fungal growth, these antifungal drugs directly activate the host's innate immunity.