Role of IL-1(beta) in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice

• Published in: Toxicological sciences 2003-07, Vol.74 (1), p.93-102
• Main Authors: Islam, Zahidul, Pestka, James J
• Format: Article
• Language: English
• Subjects: Adrenocorticotropic Hormone - blood; Adrenocorticotropic Hormone - pharmacology; Animals; Apoptosis - drug effects; Corticosterone - biosynthesis; Corticosterone - blood; DNA Fragmentation - drug effects; Endotoxins - toxicity; Flow Cytometry; Interleukin-1 - biosynthesis; Interleukin-1 - blood; Interleukin-1 - physiology; Leukocytes - drug effects; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interleukin-1 - antagonists & inhibitors; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - physiology; RNA, Messenger - biosynthesis; Spleen - chemistry; Spleen - metabolism; Trichothecenes - toxicity
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfg119

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-1beta (IL-1beta) 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-1beta mRNA and IL-1beta 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 microgram/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-1beta'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-1beta-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-1beta 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.