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ToxSci Advance Access originally published online on May 28, 2003
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Toxicological Sciences 74, 93-102 (2003)
Copyright © 2003 by the Society of Toxicology

IMMUNOTOXICOLOGY

Role of IL-1ß in Endotoxin Potentiation of Deoxynivalenol-Induced Corticosterone Response and Leukocyte Apoptosis in Mice

Zahidul Islam* and James J. Pestka*,{dagger},{ddagger},1

* Department of Food Science and Human Nutrition, {dagger} Department of Microbiology and Molecular Genetics, and {ddagger} Institute of Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824

Endotoxin (lipopolysaccharide, LPS) and the trichothecenes are microbial toxins that are frequently encountered in food and the environment. Coexposure 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-1ß (IL-1ß) plays a central role in corticosterone induction and subsequent leukocyte apoptosis in this model. Coexposure to LPS (0.1 mg/kg, ip) plus DON (12.5 mg/kg, po) was found to significantly upregulate splenic IL-1ß mRNA and IL-1ß 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 coexposure to LPS plus DON than did corresponding wild-type (WT) C57BL/6J mice. Consistent with these findings, IL-1 receptor 1-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 µg/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-1ß’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-1ß-injected mice were significantly higher at 12 h than in 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-1ß 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.

Key Words: lipopolysaccharide; immunotoxicology; apoptosis; deoxynivalenol; vomitoxin; trichothecene; mycotoxin; thymus; Peyer’s patch; bone marrow; IL-1ß; corticosterone.


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