Journal Article

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

Zahidul Islam and James J. Pestka

in Toxicological Sciences

Volume 74, issue 1, pages 93-102
Published in print July 2003 | ISSN: 1096-6080
Published online July 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg119
Role of IL-1β in Endotoxin Potentiation of Deoxynivalenol-Induced Corticosterone Response and Leukocyte Apoptosis in Mice

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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-1β (IL-1β) 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-1β mRNA and IL-1β 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-1β’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-1β-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-1β 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.

Keywords: lipopolysaccharide; immunotoxicology; apoptosis; deoxynivalenol; vomitoxin; trichothecene; mycotoxin; thymus; Peyer’s patch; bone marrow; IL-1β; corticosterone

Journal Article.  7604 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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