Cellular and molecular mechanisms for immune modulation

Volume 153, Issue 1 , 10 October 2004, Pages 61-73
Trichothecenes with a special focus on DON

Copyright 2004 ILSI. Published by Elsevier Ireland Ltd.
Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox

James J. Pestka, , a, b, c, Hui-Ren Zhoua, Y. Moona, c and Y. J. Chunga, c

a Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Food Science and Human Nutrition Bldg., East Lansing, MI 48824-1224, USA
b Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824-1224, USA
c Institute for Environmental Toxicology, Michigan State University, East Lansing, MI 48824-1224, USA

Available online 2 July 2004.

Macrophages, T cells, and B cells of the immune system are central targets of deoxynivalenol (DON) and other trichothecenes-mycotoxins that can be immunostimulatory or immunosuppressive depending on dose, exposure frequency and timing of functional immune assay. Notably, low dose trichothecene exposure transcriptionally and post-transcriptionally upregulates expression of cytokines, chemokines and inflammatory genes with concurrent immune stimulation, whereas high dose exposure 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, our laboratory has 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 second transducer is hematopoetic cell kinase (Hck), a non-receptor associated Src family kinase. Inhibitors and gene silencing studies have revealed that Hck and PKR play roles in DON induced gene expression and apoptosis. Future studies should focus on the molecular linkages between these kinases and trichothecene toxicity.

Author Keywords: Mycotoxin; Trichothecene; Deoxynivalenol; Vomitoxin; mRNA; Gene expression; Apoptosis; Immunotoxicity; Leukocyte; Kinases