Cyclooxygenase-2 mediates interleukin-6 upregulation by vomitoxin (deoxynivalenol) in vitro and in vivo.
Interleukin-6 (IL-6) is a central mediator of immunotoxicity that is associated with exposure to the trichothecene vomitoxin (VT). The purpose of this investigation was to test the hypothesis that the inducible cyclooxygenase-2 (COX-2) and its metabolites contribute to VT-induced IL-6 upregulation. VT at 100 to 250 ng/ml readily induced COX-2 protein expression in the RAW 264.7 murine macrophage cell line. Superinduction of lipopolysaccharide (LPS)-mediated IL-6 production by VT in these cells was significantly reduced by the COX inhibitors indomethacin and NS-398, whereas the inhibitors did not affect direct induction of IL-6 by LPS alone. Mice that had been gavaged orally with 5 and 25 mg/kg VT exhibited elevated COX-2 mRNA expression in Peyer's patches and spleen with peak induction occurring 2 h after VT exposure. IL-6 mRNA was also induced by VT in vivo, however, peak expression occurred from 2 to 4 h after toxin exposure, suggesting that maximal COX-2 gene upregulation preceded or was concurrent with that for IL-6. Also consistent with a putative contributory role for COX-2 was the finding that both induction of splenic IL-6 mRNA and serum IL-6 by VT were significantly reduced by pretreating mice with the COX inhibitors indomethacin or NS-398. Finally, COX-2 knockout mice showed significantly reduced splenic IL-6 mRNA and serum IL-6 responses to oral VT exposure compared to their parental wild type. Taken together, these in vitro and in vivo data suggest that VT-induced COX-2 gene expression and resultant COX-2 metabolites contributed, in part, to subsequent upregulation of IL-6 gene expression, which has been previously shown to be a hallmark of VT-mediated immunotoxicity.
Moon
Yuseok
Y
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824-1224, USA.
Pestka
James J
JJ
D000818:Animals; D003433:Crosses, Genetic; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000494:pharmacology; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014255:Trichothecenes / Q000276:immunology / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D014255:Trichothecenes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C007262:deoxynivalenol; D007213:Indomethacin