title: Endotoxin potentiation of trichothecene-induced lymphocyte apoptosis is mediated by up-regulation of glucocorticoids.
abstract: Exposure to bacterial endotoxin (lipopolysaccharide, LPS) is quite common and may increase human susceptibility to chemical-induced tissue injury. The purpose of this study was to identify mechanisms by which LPS potentiates lymphoid tissue depletion in B6C3F1 mice exposed to the common food-borne trichothecene mycotoxin, vomitoxin (VT). As demonstrated by DNA fragmentation and flow cytometric analysis, apoptosis in thymus, Peyer's patches, and bone marrow was marked in mice 12 h after administering Escherichia coli LPS (0.1 mg/kg body wt ip) concurrently with VT (12.5 mg/kg body wt po), whereas apoptosis in control mice or mice treated with either toxin alone was minimal. Based on observed increases in tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 serum concentrations following LPS and VT cotreatment, the roles of these cytokines in apoptosis potentiation were assessed. Injection with rolipram, an inhibitor of TNF-alpha expression, or use of IL-6 knockout mice was ineffective at impairing thymic apoptosis induction by the toxin cotreatment, suggesting that these cytokines did not mediate LPS potentiation. Toxin cotreatment increased splenic cyclooxygenase-2 mRNA expression, suggesting possible involvement of prostaglandins in apoptosis. However, indomethacin, a broad spectrum inhibitor of cyclooxygenases, failed to block thymus apoptosis. Toxin cotreatment increased serum corticosterone and, furthermore, RU 486, a glucocorticoid receptor antagonist, significantly abrogated apoptosis in thymus, Peyer's patches, and bone marrow following LPS + VT exposure. The results presented herein and the known capacity of glucocorticoids to cause apoptosis indicate that hypothalamic-pituitary-adrenal axis plays a key role in LPS potentiation of trichothecene-induced lymphocyte apoptosis.
authors.affiliation: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA.
authors.forename: Zahidul
authors.initials: Z
authors.lastname: Islam
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Moon
authors.forename: Hui-Ren
authors.initials: HR
authors.lastname: Zhou
authors.forename: Louis E
authors.initials: LE
authors.lastname: King
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Fraker
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003345:Corticosterone / Q000096:biosynthesis* / Q000097:blood; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004926:Escherichia coli / Q000276:immunology; D005434:Flow Cytometry; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood / Q000172:deficiency / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D014255:Trichothecenes / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D014255:Trichothecenes; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C007262:deoxynivalenol; D003345:Corticosterone; D007213:Indomethacin