Role of altered arachidonic acid metabolism in 2,3,7, 8-tetrachlorodibenzo-p-dioxin-induced immune suppression in C57Bl/6 mice.
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 inhibitors were then used to address the in vivo role of TCDD-induced changes in AA metabolism. While these inhibitors blocked AA metabolism, they failed to affect the TCDD-induced suppression of either the cytotoxic T lymphocyte response to P815 tumor cells or antibody formation in response to sheep red blood cells. The lack of effect of TCDD on cox expression, combined with the failure of metabolic inhibitors to reverse the suppression caused by TCDD, supports the conclusion that TCDD immunotoxicity is likely not mediated by a direct effect on the production of immunomodulatory AA metabolites.
Lawrence
B P
BP
College of Pharmacology, Washington State University, Pullman, Washington, 99164, USA. lawrencp@bcc.orst.edu
Kerkvliet
N I
NI
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced* / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism
D007375:Interleukin-1; D000072317:Polychlorinated Dibenzodioxins; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone