Cyclooxygenase-2 mediates interleukin-6 upregulation by vomitoxin (deoxynivalenol) in vitro and in vivo.

Abstract:

: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.

journal_name

Toxicol Appl Pharmacol

authors

Moon Y,Pestka JJ

doi

10.1016/s0041-008x(02)00033-9

subject

Has Abstract

pub_date

2003-03-01 00:00:00

pages

80-8

issue

2

eissn

0041-008X

issn

1096-0333

pii

S0041008X02000339

journal_volume

187

pub_type

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