ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg119
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824
* To whom correspondence should be addressed. E-mail: pestka{at}pilot.msu.edu.
Endotoxin (lipopolysaccharide, LPS) and the trichothecenes are microbial toxins that are frequently encountered in food and the environment. Co-exposure to LPS and the trichothecene deoxynivalenol (DON, vomitoxin) induces corticosterone-dependent apoptosis in thymus, Peyer's patches, and bone marrow in mice. The purpose of this study was to test the hypothesis that interleukin-1
© 2003 Society of Toxicology
Immunotoxicology
Role of IL-1
in Endotoxin Potentiation of Deoxynivalenol-Induced Corticosterone Response and Leukocyte Apoptosis in Mice
2 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824; Institute of Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824
Abstract 
(IL-1) plays a central role in corticosterone induction and subsequent leukocyte apoptosis in this model. Co-exposure to LPS (0.1 mg/kg, ip) plus DON (12.5 mg/kg, po) was found to significantly upregulate splenic IL-1 mRNA and IL-1 protein expression in B6C3F1 mice, as compared to treatments with vehicle or either of the toxins alone. B6.129S7-IL1r1tm1Imx mice, which are functionally deficient for the IL-1 receptor 1, produced significantly less corticosterone upon co-exposure to LPS plus DON than did corresponding wild-type C57BL/6J mice. Consistent with these findings, IL-1 receptor1-deficient mice were recalcitrant to apoptosis induction in leukocytes as determined by assessment of DNA fragmentation assay and flow cytometry. Furthermore, intraperitoneal injection of IL-1 receptor antagonist (100 :g/mouse, twice at 3 h intervals) in B6C3F1 mice significantly inhibited LPS plus DON-induced increases in plasma corticosterone as well as apoptosis in thymus, Peyer's patches and bone marrow. To confirm IL-1's capacity to induce apoptosis, B6C3F1 mice were injected with the cytokine (500 ng/mouse, ip) three times at 2 h intervals and then corticosterone and apoptosis were monitored. Plasma corticosterone levels and thymus and Peyer's patch apoptosis in IL-1 - injected mice were significantly higher at 12 h than control mice. Plasma adrenocorticotropic hormone (ACTH) levels in LPS plus DON-treated B6C3F1 mice did not correlate with the induction of plasma corticosterone or leukocyte apoptosis. Taken together, the results indicate that IL-1 is an important mediator of LPS plus DON-induced corticosterone and subsequent leukocyte apoptosis and, furthermore, this cytokine possibly acts through an ACTH-independent mechanism., corticosterone
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