Enniatin B-induced cell death and inflammatory responses in RAW 267.4 murine macrophages
- Norwegian Veterinary Institute, P.O. Box 750, Centrum, N-0106 Oslo (Norway)
- EA 4427 SeRAIC, IRSET, Université de Rennes 1, IFR 140, Rennes (France)
- Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, N-0403 Oslo (Norway)
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-1β) 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-1β and possibly activation of the inflammasome through lysosomal damage and leakage of cathepsin B. -- Highlights: ► The mycotoxin EnnB induced cell cycle arrest, cell death and inflammation. ► The G0/G1-arrest was linked to a reduced ability to internalize receptors. ► EnnB caused lysosomal damage, leakage of cathepsin B and caspase-1 cleavage. ► Caspase-1 was partly involved in both apoptosis and release of IL-1β. ► There was a synergistic action between EnnB and bacterial LPS.
- OSTI ID:
- 22215317
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 261; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
AMINES
APOPTOSIS
CATHEPSINS
CELL CYCLE
CHOLERA
CHOLESTEROL
DMSO
DNA
FUSARIUM
GUANOSINE
INFLAMMATION
IODIDES
LYMPHOKINES
LYSOSOMES
MACROPHAGES
MOLYBDENUM NITRIDES
MORPHOLOGY
MYCOTOXINS
MYELIN
OXYGEN
PATHOGENS
PATTERN RECOGNITION
PYRAZINES
RECEPTORS
TRANSMISSION ELECTRON MICROSCOPY