Mechanisms of deoxynivalenol-induced gene expression and apoptosis

Abstract

Fusarium infection of agricultural staples such as wheat, barley and corn with concurrent production of deoxynivalenol (DON) and other trichothecene mycotoxins is an increasingly common problem worldwide. In addition to its emetic effects, chronic dietary exposure to DON causes impaired weight gain, anorexia, decreased nutritional efficiency and immune dysregulation in experimental animals. Trichothecenes are both immunostimulatory or immunosuppressive depending on dose, frequency and duration of exposure as well as type of immune function assay. Monocytes, macrophages, as well as T and B lymphocytes of the immune system can be cellular targets of DON and other trichothecenes. In vitro exposure to low trichothecene concentrations upregulates expression both transcriptionally and post-transcriptionally of cytokines, chemokines and inflammatory genes with concurrent immune stimulation, whereas exposure to high concentrations promotes leukocyte apoptosis with concomitant immune suppression. DON and other trichothecenes, via a mechanism known as the "ribotoxic stress response", bind to ribosomes and rapidly activate mitogen-activated protein kinases (MAPKs). The latter are important transducers of downstream signaling events related to immune response and apoptosis. Using cloned macrophages, we have identified two critical upstream transducers of DON-induced MAPK activation. One transducer is double-stranded RNA-(dsRNA)-activated protein kinase (PKR), a widely-expressed serine/theonine protein kinase that can be activated by dsRNA, interferon and other agents. The other transducer is hematopoetic cell kinase (Hck), a non-receptor associated Src oncogene family kinase. Pharmacologic inhibitors and gene suppression studies have revealed that Hck and PKR contribute to DON-induced gene expression and apoptosis. PKR, Hck and other kinases bind to the ribosome and are activated following DON interaction. Future studies will focus on the sequence of molecular events at the ribosome level that drive selective activation of these upstream kinases.

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

“…In his review, Pestka (2008) summarised the genes with a lower mRNA decay rate upon DON administration, which are COX-2, tumour necrosis factor (TNF)-a and interleukin (IL)-6 in macrophages and IL-2 in EL-4T-cells. It has been reported that all four mRNAs are stabilised by ARE in the 3 0 untranslated region (Chen et al, 2001, Paschoud et al, 2006, Rajasingh et al, 2006.…”

The mycotoxin deoxynivalenol promotes uptake ofSalmonellaTyphimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization

“…However, many of their toxic effects might also be related to a rapidly ensuing dysregulation of intracellular cell signaling and consequent alterations in downstream gene expression [27]. Exposure to low levels of trichothecenes appears to promote expression of a diverse array of cytokines and proinflammatory genes in vitro and in vivo via a mechanism known as the ribotoxic stress response that involves multiple intracellular signaling cascades [26,38,39].…”

In vivo effect of deoxynivalenol (DON) naturally contaminated feed on porcine reproductive and respiratory syndrome virus (PRRSV) infection

“…DON has a unique effect on immune system as it has the 15 capacity to up and down regulate immune function depending on dose, exposure 16 frequency, timing and the functional immune assay being employed (Pestka, 2008). The infection (Ramos et al, 2010).…”