Abstract
Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E2 (PGE2)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection.
Highlights
Zearalenone (ZEA), a non-steroidal estrogenic mycotoxin, is produced by several species of Fusarium fungi that widely contaminate many cereal crops including wheat, corn, sorghum, oats, and barley, and subsequently produce ZEA at low temperatures and high humidity environments [1]
Mycotoxins are toxic secondary metabolites produced by fungi duced by fungi and found in many agricultural commodities that have unlike toxic effects and found in many agricultural commodities that have unlike toxic effects according to according to the toxin and concentration and result in immunostimulatory or immunothe toxin and concentration and result in immunostimulatory or immunosuppressive suppressive effects [18]
The NLRP3 inflammasome activation in macrophages was induced by LPS/ATP and LPS/nigericin, thereby inducing the secretion of IL-1β, enhancing the expression of cleaved caspase-1 and cleaved IL-1β, and increasing the colocalization of ASC and caspase-1, whereas ZEA significantly attenuated the activation of NLRP3 inflammasome by LPS/ATP- and LPS/nigericin-activated macrophages through decreasing the secretion of IL-1β, suppressing the expression of cleaved caspase-1 and cleaved IL-1β, and reducing the colocalization of ASC and caspase-1. These results suggest that ZEA might diminish the activation of NLRP3 inflammasome in macrophages during bacterial infection
Summary
Zearalenone (ZEA), a non-steroidal estrogenic mycotoxin, is produced by several species of Fusarium fungi that widely contaminate many cereal crops including wheat, corn, sorghum, oats, and barley, and subsequently produce ZEA at low temperatures and high humidity environments [1]. While ZEA exhibits low acute toxicity (oral LD50 > 2000 mg/kg body weight [3]), long-term exposure to ZEA has several harmful effects due to its toxicity and high estrogenic activity including immunotoxic [4], hepatotoxic [5], and genotoxic [6] effects; the effect of ZEA on regulation of immune responses has not been well evaluated. The innate immunity acts as the first line of defense against pathogen infection, and macrophages are antigen-presenting cells in the innate immune system that can phagocytose bacteria and produce both proinflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6), and mediators (e.g., nitric oxide (NO) and cyclooxygenase-2 (COX-2, a key enzyme in the synthesis of prostaglandins)) [7]. Macrophages recognize pathogen-associated molecular patterns (e.g., lipopolysaccharide (LPS)) and damage-associated molecular patterns (e.g., adenosine triphosphate (ATP) and nigericin) by pathogen recognition receptors (e.g., tolllike receptors (TLRs)) and subsequently activate the downstream mitogen-activated protein kinases (MAPKs, such as the c-Jun amino-terminal kinase (JNK), the extracellular signalregulated protein kinase (ERK), the p38 MAP kinase (p38)) and transcription factors (e.g., nuclear factor-κB (NF-κB)) to regulate immune responses against pathogen infection [8,9]
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