The mycotoxin enniatin B (EnnB) is predominantly produced by species of the Fusarium genera, and often found in grain. The cytotoxic effect of EnnB has been suggested to be related to its ability to form ionophores in cell membranes. The present study examines the effects of EnnB on cell death, differentiation, proliferation and pro-inflammatory responses in the murine monocyte-macrophage cell line RAW 264.7. Exposure to EnnB for 24 h caused an accumulation of cells in the G0/G1-phase with a corresponding decrease in cyclin D1. This cell cycle-arrest was possibly also linked to the reduced cellular ability to capture and internalize receptors as illustrated by the lipid marker ganglioside GM1. EnnB also increased the number of apoptotic, early apoptotic and necrotic cells, as well as cells with elongated spindle-like morphology. The Neutral Red assay indicated that EnnB induced lysosomal damage: supported by transmission electron microscopy (TEM) showing accumulation of lipids inside the lysosomes forming lamellar structures/myelin bodies. Enhanced levels of activated caspase-1 were observed after EnnB exposure and the caspase-1 specific inhibitor ZYVAD-FMK reduced EnnB-induced apoptosis. Moreover. EnnB increased the release of interleukin-1beta (IL-1 beta) in cells primed with lipopolysaccharide (LPS), and this response was reduced by both ZYVAD-FMK and the cathepsin B inhibitor CA-074Me. In conclusion, EnnB was found to induce cell cycle arrest, cell death and inflammation. Caspase-1 appeared to be involved in the apoptosis and release of IL-1 beta and possibly activation of the inflammasome through lysosomal damage and leakage of cathepsin B. Published by Elsevier Inc.
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Droga-Mazovec, Gabriela
Bojic, Lea
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Bojic, Lea
Petelin, Ana
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Petelin, Ana
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Ivanova, Saska
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Romih, Rok
Repnik, Urska
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Repnik, Urska
Salvesen, Guy S.
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Burnham Inst Med Res, La Jolla, CA 92037 USAJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Salvesen, Guy S.
Stoka, Veronika
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Stoka, Veronika
Turk, Vito
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Turk, Vito
Turk, Boris
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Droga-Mazovec, Gabriela
Bojic, Lea
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Bojic, Lea
Petelin, Ana
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Petelin, Ana
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Ivanova, Saska
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Romih, Rok
Repnik, Urska
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Repnik, Urska
Salvesen, Guy S.
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Burnham Inst Med Res, La Jolla, CA 92037 USAJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Salvesen, Guy S.
Stoka, Veronika
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Stoka, Veronika
Turk, Vito
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia
Turk, Vito
Turk, Boris
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Jozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, SloveniaJozef Stefan Inst, Dept Biochem Mol & Struct Biol, SI-1000 Ljubljana, Slovenia