Induction of cytokine gene expression in mice after repeated and subchronic oral exposure to vomitoxin (Deoxynivalenol): differential toxin-induced hyporesponsiveness and recovery.
A single oral exposure to vomitoxin (VT) in mice has been previously shown to induce in lymphoid tissues the rapid expression of cytokine mRNAs that are produced by both macrophages and T cells. To determine whether prior VT exposures positively or negatively modulate the cytokine response to the toxin in this model, we evaluated the effects of short-term oral (two to seven consecutive daily doses) and subchronic dietary (4 weeks) exposure to VT on expression of a panel of cytokine mRNAs. Effects of a single oral exposure to 0, 5, and 25 mg/kg body wt of VT or of two such daily consecutive doses on splenic cytokine mRNA abundance were compared 2 h after the last toxin administration using RT-PCR in combination with hybridization analysis. While robust cytokine mRNA responses occurred after a single VT exposure, attenuated but significant induction of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-12p40 mRNA was observed after a second VT dose. Similar but insignificant trends occurred with interferon (IFN)-gamma, IL-2, IL-4, and IL-10 mRNAs. Serum TNF-alpha and IL-6 proteins mimicked cytokine mRNA responses although attenuation responses were less marked. Mice were also dosed with VT at 0, 0.5, 2, or 5 mg/kg body wt consecutively for 2, 4, or 7 days and cytokine mRNAs were assessed 2 h after the last treatment in spleen and Peyer's patches. Upon exposure to 2 and 5 mg/kg body wt VT, the relative abundance of IL-1beta, IL-6, TNF-alpha, IL-12 p35, IL-12p40, IL-2, and IL-10 mRNAs increased with dose frequency whereas IFN-gamma and IL-4 mRNAs were unaffected. When mice were fed 0, 10, and 25 ppm VT for 4 weeks, increased expression of mRNAs for TNF-alpha, IL-2, IFN-gamma, and IL-10 was most prominent. However, when VT-fed mice were also challenged with an oral dose of VT equivalent to daily intake at 2 h prior to RNA isolation, vigorous mRNA responses were observed for IL-1beta, IL-6, TNF-alpha, IL-12p40, IL-12p35, IL-2, IFN-gamma, IL-4, and IL-10. In general, spleens were more responsive to the above effects than Peyer's patches. The results indicate that, following a single prior VT exposure, a significant but attenuated cytokine mRNA response occurred upon a second VT treatment. This hyporesponsiveness was overcome upon repeated exposures to the toxin. These data further support the contention that elevated cytokine expression may play a contributory role in the pathophysiologic and immunologic effects of VT and other trichothecene mycotoxins.
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824, USA.
H R
HR
Zhou
D
D
Yan
J J
JJ
Pestka
D000284:Administration, Oral; D000818:Animals; D016207:Cytokines / Q000235:genetics*; D004032:Diet; D004731:Endotoxins / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D009183:Mycotoxins / Q000633:toxicity; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014255:Trichothecenes / Q000008:administration & dosage / Q000494:pharmacology*
D016207:Cytokines; D004731:Endotoxins; D009183:Mycotoxins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014255:Trichothecenes; C007262:deoxynivalenol