Mechanisms of deoxynivalenol-induced gene expression and apoptosis.
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 signalling events related to immune response and apoptosis. Using cloned macrophages, two critical upstream transducers of DON-induced MAPK activation have been identified. One transducer is double-stranded RNA (dsRNA)-activated protein kinase (PKR), a widely expressed serine/threonine protein kinase that can be activated by dsRNA, interferon and other agents. The other transducer is haematopoetic cell kinase (Hck), a non-receptor associated Src oncogene family kinase. Pharmacological 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.
Pestka
J J
JJ
Center for Integrative Toxicology, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA. Pestka@msu.edu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D005506:Food Contamination; D005786:Gene Expression Regulation / Q000187:drug effects*; D006128:Growth / Q000187:drug effects; D006801:Humans; D055633:Immune System Phenomena / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D009183:Mycotoxins / Q000494:pharmacology* / Q000633:toxicity; D014255:Trichothecenes / Q000494:pharmacology* / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D009183:Mycotoxins; D014255:Trichothecenes; C007262:deoxynivalenol