Activation of the Ah receptor signaling pathway by prostaglandins.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of a diverse range of chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Although no endogenous physiological ligand for the AhR has yet been described, numerous studies support the existence of such a ligand(s). Here we have examined the ability of prostaglandins and related chemicals to activate the AhR signaling system. Using two AhR-based bioassay systems we report that relatively high concentrations of several prostaglandins (namely, PGB3, PGD3, PGF3alpha, PGG2, PGH1, and PGH2) can not only stimulate AhR transformation and DNA binding in vitro, but also induce AhR-dependent reporter gene expression in mouse hepatoma cells in culture. PGG2 also induced AhR-dependent reporter gene expression to a level three-to four fold greater than that observed with a maximal inducing dose of TCDD. Sucrose gradient ligand binding analysis revealed that PGG2 could competitively displace [3H]TCDD from the AhR. Overall, our results demonstrate that selected prostaglandins are weak agonists for the AhR and they represent a structurally distinct and novel class of activator of the AhR signal transduction pathway.
Seidel
S D
SD
Department of Environmental Toxicology, University of California, Davis, 95616-8588, USA.
Winters
G M
GM
Rogers
W J
WJ
Ziccardi
M H
MH
Li
V
V
Keser
B
B
Denison
M S
MS
D000818:Animals; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D002850:Chromatography, Gel; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013395:Sucrose
D000072317:Polychlorinated Dibenzodioxins; D011453:Prostaglandins; D018336:Receptors, Aryl Hydrocarbon; D013395:Sucrose; D004247:DNA; D008156:Luciferases; D015232:Dinoprostone