title: Role of IL-1(beta) in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice.
abstract: 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.
authors.affiliation: Department of Food Science and Human Nutrition, Institute of Environmental Toxicology, Michigan State University, East Lansing, Michigan, 48824, USA.
authors.forename: Zahidul
authors.initials: Z
authors.lastname: Islam
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003345:Corticosterone / Q000096:biosynthesis* / Q000097:blood; D053938:DNA Fragmentation / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D005434:Flow Cytometry; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D007962:Leukocytes / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000737:chemistry / Q000378:metabolism; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D014255:Trichothecenes; D000324:Adrenocorticotropic Hormone; C007262:deoxynivalenol; D003345:Corticosterone