title: Differential cytokine mRNA expression in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): dose response and time course.
abstract: Acute oral exposure of B6C3F1 mice to vomitoxin (VT) has been previously shown to induce expression of mRNAs for cytokines that are characteristically produced in lymphoid tissues by macrophage and T cells. The purpose of this study was to evaluate the effects of VT dose on the expression of mRNAs for a cytokine profile consisting of TNF-alpha, IL-1beta, IL-6, IL-12, IFN-gamma, IL-2, IL-4, IL-5, IL-10, IL-12, and TGF-beta and to measure the kinetics of these responses. The effects of a single oral exposure to 0, 0.1, 0.5, 1, 5, and 25 mg/kg BW of VT on cytokine mRNA abundance in spleen and Peyer's patches (indicators of systemic and mucosal immune compartments, respectively) were assessed at 2 hr postexposure using reverse transcriptase-polymerase chain reaction (RT-PCR) in combination with hybridization analysis. Both 5 and 25 mg/kg VT significantly induced the mRNAs for the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha; the T helper 1 cytokines IFN-gamma and IL-2; and the T helper 2 cytokines IL-4 and IL-10, whereas lower doses had no effect. IL-12p40 mRNA was also induced but not IL-12p35 mRNA. The effects were more pronounced in spleen than in the Peyer's patches. IL-5 and TGF-beta mRNAs were expressed constitutively in spleen and Peyer's patches but were not affected by VT. When cytokine mRNA levels were measured at 1, 2, 4, 8, and 24 hr after oral exposure to 25 mg/kg BW of VT, mRNA expression kinetics varied among cytokines or between spleen and Peyer's patches. The duration of elevated mRNA expression in spleen was 1-8 hr for TNF-alpha, IL-6, IFN-gamma, and IL-10 and was 1-4 hr for IL-1beta, IL-12p40, IL-2, and IL-4. In Peyer's patches, duration periods were 1-8 hr for IL-6, IL-2, and IL-10; 1-4 hr for IL-1beta, IL-12p40, and TNF-alpha; and 1-2 hr for IFN-gamma. Serum levels of TNF-alpha, IL-6, and IFN-gamma were elevated 3 hr after exposure to 25 mg/kg VT, thus suggesting that elevation of splenic and Peyer's patch mRNA abundance correlated with increases in systemic production of these cytokines. Taken together, the results indicate that a single VT exposure rapidly induces gene expression in vivo for a wide range of cytokines with apparently complete recovery occurring after 24 hr. Elevated cytokine expression may play an important role in the pathophysiologic effects of VT and other trichothecenes.
authors.affiliation: Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Zhou
authors.forename: D
authors.initials: D
authors.lastname: Yan
authors.forename: J J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D015342:DNA Probes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D007700:Kinetics; D008297:Male; D051379:Mice; D010581:Peyer's Patches / Q000187:drug effects / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014255:Trichothecenes / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D015342:DNA Probes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014255:Trichothecenes; C007262:deoxynivalenol