Abstract
Fusaric acid (FA), a food-borne mycotoxin, is a potent divalent metal chelator. The human immune system is complex and susceptible to environmental insult however, the immunotoxity of FA remains unknown. We investigated the immunotoxicity of FA on human peripheral blood mononuclear cells (PBMCs) and Thp-1 cells. FA was cytotoxic to PBMCs (IC50-240.8 μg/ml) and Thp-1 (IC50-107.7 μg/ml) cells at 24 h. FA induced early apoptosis but significantly decreased caspase activity in PBMCs, a characteristic of paraptosis. In Thp-1 cells, FA induced apoptosis and increased caspase −9 and −3/7 activities. In PBMCs, FA maintained mitochondrial membrane potential and decreased protein expression of Bax whilst increasing expression of p-Bcl-2; FA induced oxidative stress and depleted ATP levels in both cell types. In Thp-1 cells, FA increased mitochondrial membrane depolarization and decreased p-Bcl-2 expression. In PBMCs, FA significantly up-regulated the MAPK protein expression of p-ERK and p-JNK but down-regulated p-p38 expression. In Thp-1 cells, FA up-regulated MAPK protein expression of p-ERK whilst p-JNK and p-p38 expression were down-regulated. In conclusion FA induced programmed cell death and altered MAPK signaling in healthy PBMCs and Thp-1 cells strongly suggesting a possible mechanism of FA induced immunotoxicity in vitro.
Highlights
Endophytic fungi produce mycotoxins that are toxic to animals and humans[1]
The mitogen-activated protein kinases (MAPKs) family comprises of three universal serine/threonine protein kinases; these include the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase[15, 16]; each group of MAPK is activated via a series of phosphorylation events[16]
This study shows that Fusaric acid (FA), a common food borne mycotoxin, is toxic to the human immune system
Summary
Fusaric acid (FA, 5-butylpicolinic acid), is a picolinic acid derivative produced by several strains of Fusarium species[2, 3] These fungal strains are ubiquitous in soil and are known to parasitize maize and many other cereal grains[4, 5]. In response to foreign particle or pathogen, several signaling pathways are activated in immune cells[12]. Foremost of these pathways, is the activation of mitogen-activated protein kinases (MAPKs)[12]. MAPK activity directs diverse immune responses ranging from stress, cell death/survival and immune defense[12,13,14]. Optimal cellular mitochondrial function increases ATP synthesis and reactive oxygen species (ROS) that mediate cell signaling pathways[8]. Paraptosis is distinct from necrotic and apoptotic cell death and its features are defined by the lack of apoptotic morphology and independent of caspase activation[19, 22, 23, 25,26,27]
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