Immunomodulatory effects of individual and combined mycotoxins in the THP-1 cell line

Abstract

Mycotoxins commonly contaminate food and may pose a risk for disease in humans and animals. As they frequently co-occur, mixed exposures often take place. Monocyte function, including differentiation into active macrophages, is a central part of the immune response. Here we studied effects of naturally co-occurring mycotoxins in grain on monocyte function, and effects of individual and combined exposure on the differentiation process from monocytes into macrophages. The THP-1 cell line was used as a model system. The mycotoxins 2-amino-14,16-dimethyloctadecan-3-ol (AOD), alternariol (AOH), enniatin B (ENNB), deoxynivalenol (DON), sterigmatocystin (ST) and zearalenone (ZEA) differently affected cell viability in THP-1 monocytes, with DON as the most potent. AOH, ZEA and DON inhibited differentiation from monocytes into macrophages. Using this differentiation model, combined exposure of AOH, ZEA and DON were mainly found to be additive. However, the combination AOH+ZEA had somewhat synergistic effect at lower concentrations. Furthermore, alterations in macrophage functionality were found, as single exposure of AOH and ZEA inhibited lipopolysaccharide (LPS) induced TNF-α secretion, while DON increased this response. Overall, the mycotoxins affected monocyte viability and differentiation into macrophages differently. Combined exposures affected the differentiation process mainly additively.

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

“…Cytotoxicity of AOH was only marginal in LPS-stimulated THP-1 derived macrophages, which is in line with previous findings (Fig. 1a–d) (Pahlke et al 2016; Solhaug et al 2015, 2016; Tiessen et al 2013). In recent times, more and more light was shed on the mycotoxin AOH and its ability to manipulate the rich network of multiple biological processes needed to strategically mount a defense response.…”

“…Previously, AOH was reported to affect PMA-induced differentiation of THP-1 monocytes by reducing the expression of CD14 and CD11b, indicating a potentially reduced immune response. Indeed, in the same study, AOH (15 µM) diminished the immune response to LPS by alleviating secretion of the proinflammatory cytokine TNF-α (Solhaug et al 2016). Interestingly, in the present study we observed a substantial suppression of the LPS-induced NF-κB pathway activation after AOH (1–20 µM) exposure in differentiated THP-1 derived macrophages, which presumably may explain the previously observed immunosuppressive effects of AOH (Fig.…”

“…Besides glucocorticoids (e.g., dexamethasone) that are known to inhibit inflammatory processes by targeting NF-κB, in recent years a vast number of naturally occurring compounds (e.g., polyphenols, mycotoxins, isothiocyanates) was also found to possess potential immunosuppressive effects (Kundu et al 2006; Moon et al 2009; Smoak and Cidlowski 2004; Solhaug et al 2016). Mycotoxins are naturally occurring secondary metabolites produced by a variety of fungal species that contaminate food and feed commodities and thus, might pose a risk to human and animal health (EFSA 2011).…”

“…Consequently, EFSA emphasized the necessity of additional data to characterise a potential hazard arising from AOH exposure (EFSA 2016). Moreover, recent studies reported AOH to exhibit immunosuppressive properties in vitro by modifying the expression of CD receptors and proinflammatory cytokines (Grover and Lawrence 2017; Solhaug et al 2016). More specifically, AOH impaired the differentiation from monocytes to macrophages by reducing the expression of CD14 and CD11b.…”

“…Therefore, a reduced macrophage differentiation during inflammation might generate serious losses in the hosts’ immune system, depleting the implementation of an effective immune response. Additionally, Solhaug et al found a reduced response of THP-1 derived macrophages to LPS after exposure to AOH, characterised by reduced secretion and transcription of the proinflammatory cytokine TNF-α (Solhaug et al 2016). AOH has been reported to reduce gene expression of proinflammatory cytokines (IL-8, IL-6) also in other cell models (RAW264.7 macrophages and BEAS-2B human bronchial lung epithelial cells); however, the underlying mechanisms responsible for the immunosuppressive effects induced by AOH have not been identified so far (Grover and Lawrence 2017).…”