RESUMEN
Repression of cancer-protective phase II enzymes may help explain why estrogen exposure leads to the development of cancer. In an earlier report we described the ability of 17beta-estradiol (E(2)) to repress phase II enzyme activity in vivo. Phase II enzymes are coordinately regulated via the presence of the antioxidant response element (ARE) in their promoter. We wanted to determine if estrogen receptors (ER) repress ARE-dependent gene expression through a mechanism that requires interaction with Nrf2, the transcription factor that regulates ARE-mediated gene transcription. E(2)-bound ERalpha, but not ERbeta, represses ARE-regulated gene expression in the presence of exogenously expressed Nrf2 as well as when the transactivation domain of Nrf2 was fused to a heterologous DNA-binding domain. Deletion of the activation function-2 (AF-2) and the ligand-binding domain of ERalpha result in a constitutive repression of Nrf2-mediated transcription. Finally, E(2)-bound ERalpha co-immunoprecipitates with Nrf2. Repression of Nrf2-mediated transcription by E(2)-bound ERalpha expands our knowledge of E(2)-regulated genes and provides a potential drug-screening target for the development of selective estrogen receptor modulators with a lower risk of causing cancer.
Asunto(s)
Antioxidantes/fisiología , Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Regulación de la Expresión Génica , Factor 2 Relacionado con NF-E2/metabolismo , Elementos de Respuesta , Animales , Línea Celular , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Silenciador del Gen , Genes Reporteros , Humanos , Ligandos , Factor 2 Relacionado con NF-E2/genética , Proteínas Nucleares/metabolismoRESUMEN
Diets rich in soy phytoestrogens have many potential health benefits but isoflavones such as genistein may suppress cell mediated immune function. The effect of dietary phytoestrogens on the host response to infection has not been extensively examined. Mice were fed a diet containing soy phytoestrogens and infected with Mycobacterium avium to establish a chronic infection and inflammatory response. As phytoestrogens may act through classical oestrogen receptors (ER), mice deficient in ERalpha signalling and wild type mice were evaluated for a panel of Type 1-associated cytokines (IFNgamma, IL-12 and IL-18) in the spleen. IFNgamma production in the spleen was increased approximately 4-fold in ERalpha-deficient mice fed a casein-based diet over wild type mice fed a casein-based diet (P < 0.05), suggesting a role for ERalpha in suppressing IFNgamma production. IL-18 levels in spleens of wild type mice were decreased compared to ERalpha-deficient mice on a casein diet. Splenic IL-12 and IL-18 levels were not affected in wild type and ERalpha-deficient mice on the phytoestrogen containing diets, with the exception that whole soy increased IL-12 levels in the tissues of ERalpha deficient mice. We conclude that ERalpha and dietary phytoestrogens can influence production of key regulatory cytokines in response to chronic bacterial infection.