ToxSci Advance Access originally published online on July 22, 2009
Toxicological Sciences 2009 111(2):277-287; doi:10.1093/toxsci/kfp150
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Induction of Suppressors of Cytokine Signaling by the Trichothecene Deoxynivalenol in the Mouse
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* Comparative Medicine and Integrative Biology Program
Center for Integrative Toxicology
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824
Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan
1 To whom correspondence should be addressed at 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824-1224. Fax: (517) 353-8963. E-mail: Pestka{at}msu.edu.
Received April 8, 2009; accepted July 8, 2009
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Abstract |
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Deoxynivalenol (DON), a trichothecene mycotoxin found in grains and cereal–based foods worldwide, impairs weight gain in experimental animals but the underlying mechanisms remain undetermined. Oral exposure to DON induces rapid and transient upregulation of proinflammatory cytokine expression in the mouse. The latter are known to induce several suppressors of cytokine signaling (SOCS), some of which impair growth hormone (GH) signaling. We hypothesized that oral exposure to DON will induce SOCS expression in the mouse. Real-time PCR and cytokine bead array revealed that oral gavage with DON rapidly (1 h) induced tumor necrosis factor-
and interleukin-6 mRNA and protein expression in several organs and plasma, respectively. Upregulation of mRNAs for four well-characterized SOCS (CIS [cytokine-inducible SH2 domain protein], SOCS1, SOCS2, and SOCS3) was either concurrent with (1 h) or subsequent to cytokine upregulation (2 h). Notably, DON-induced SOCS3 mRNAs in muscle, spleen and liver, with CIS1, SOCS1, and SOCS2 occurring to a lesser extent. Hepatic SOCS3 mRNA was a very sensitive indicator of DON exposure with SOCS3 protein being detectable in the liver well after the onset of cytokine decline (5 h). Furthermore, hepatic SOCS upregulation was associated with about 75% suppression of GH-inducible insulin-like growth factor acid labile subunit. Taken together, DON-induced cytokine upregulation corresponded to increased expression of several SOCS, and was associated with suppression of GH-inducible gene expression in the liver.
Key Words: deoxynivalenol; SOCS3; cytokines.