Role of altered arachidonic acid metabolism in 2,3,7, 8-tetrachlorodibenzo-p-dioxin-induced immune suppression in C57Bl/6 mice

Toxicological Sciences : an Official Journal of the Society of Toxicology
B P Lawrence, N I Kerkvliet

Abstract

One of the most sensitive targets of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is the immune system. Many arachidonic acid (AA) metabolites are potent immunoregulatory molecules, and in other systems, TCDD has been shown to alter AA metabolism. Furthermore, the genes for cyclooxygenase (cox) contain a dioxin response element, suggesting that exposure to TCDD may directly alter cox levels and prostaglandin (PG)E2 production. To test the hypothesis that TCDD induces immune suppression by altering the production of immunomodulatory AA metabolites, we examined the effects of TCDD on splenic AA release, LTB4 and PGE2 production, and cox-1 and cox-2 expression. Exposure of C57Bl/6 mice to TCDD (15 microg/kg) resulted in a 2-fold increase in the release of AA from spleen cell membranes, a 1.4-fold enhancement of LTB4 and PGE2 production in the spleen, and 3-fold higher PGE2 levels in the peritoneal cavity during the immune response to allogeneic P815 tumor cells. We examined the direct induction of cox-1 and cox-2 by TCDD and the indirect induction of cox-2 via TCDD-induced IL-1. Interestingly, exposure to TCDD did not alter message or protein levels of cox-1, cox-2, or IL-1 over the course of the response to P815. Various metabolic...Continue Reading

Citations

Nov 17, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sabine TeskeB Paige Lawrence
Jan 24, 2003·Annual Review of Pharmacology and Toxicology·Michael S Denison, Scott R Nagy
Jan 21, 2012·Journal of Crohn's & Colitis·Stephanie VerschuereClaude A Cuvelier
May 9, 2013·Environmental and Molecular Mutagenesis·Sam De CosterNicolas van Larebeke

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