REGULATION OF PROSTAGLANDIN ENDOPEROXIDE-H SYNTHASE-2 EXPRESSION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

We have examined the molecular mechanisms for 2,3,7,8-tetrachlorodiben zo-p-dioxin (TCDD)-stimulated prostaglandin synthesis in Mardin Darvey canine kidney cells (MDCK), TCDD stimulates prostaglandin synthesis i n these cells, at least in part, by elevating prostaglandin endoperoxi de H-2 synthase-2 (PGHS-2) levels, TCDD-stimulated transcription of th e PGHS-2 gene was maximal (6-fold) within 2 h and resulted in a 100-fo ld increase in PGHS-2 mRNA and a 25-fold increase in PGHS-2 protein le vels by 4 h, Transient transfection experiments using luciferase-repor ter plasmids demonstrated that control element(s) responsible for TCDD activation of the murine PGHS-2 promoter in MDCK cells are located in the first 965 nucleotides upstream from the PGHS-2 transcriptional in itiation site, A canonical xenobiotic response element, similar to tho se that control transcription of other well-known TCDD-sensitive genes , is present at position -157, but does not appear to be sufficient fo r halogenated aromatic hydrocarbon (HAH) activation of the PGHS-2 prom oter, TCDD failed to stimulate transcription from the PGHS-2 promoter when reporter plasmids were transfected into Hepa 1c1c7 cells, a line which contains the functional aryl hydrocarbon receptor, It seems like ly that inappropriate expression of PGHS-2 may contribute to the toxic effects of TCDD and other HAHs, In particular, PGHS-2 expression may affect those toxic reactions that involve inappropriate cellular growt h, such as dermal hyperplasia and tumor formation, It is also likely t hat elevated synthesis of prostaglandins, which are potent regulators of immune function, could play a role in the immunotoxicity associated with HAH exposure. (C) 1996 Academic Press, Inc.