An additive interaction between the NFκB and estrogen receptor signalling pathways in human endometrial epithelial cells

Human embryo implantation is regulated by estradiol (E2), progesterone and locally produced mediators including interleukin-1 beta (IL-1 beta). Interactions between the estrogen receptor (ER) and NF kappa B (NF kappa B) signalling pathways have been reported in other systems but have not been detailed in human endometrium. Real-time PCR showed that mRNA for the p65 and p105 NF kappa B subunits is maximally expressed in endometrium from the putative implantation window. Both subunits are localized in the endometrial epithelium throughout the menstrual cycle. Reporter assays for estrogen response element (ERE) activity were used to examine functional interactions between ER and NF kappa B in telomerase immortalized endometrial epithelial cells (TERT-EEC). E2 and IL-1 beta treatment of TERT-EECs enhances ERE activity by a NF kappa B and ER dependent mechanism; this effect could be mediated by ER alpha or ER beta. E2 and IL-1 beta also positively interact to increase endogenous gene expression of prostaglandin E synthase and c-myc. This is a gene-dependent action as there is no additive effect on cyclin D1 or progesterone receptor expression. In summary, we have established that NF kappa B signalling proteins are expressed in normal endometrium and report that IL-1 beta can enhance the actions of E2 in a cell line derived from healthy endometrium. This mechanism may allow IL-1 beta, possibly from the developing embryo, to modulate the function of the endometrial epithelium to promote successful implantation, for example by regulating prostaglandin production. Aberrations in the interaction between the ER and NF kappa B signalling pathways may have a negative impact on implantation contributing to pathologies such as early pregnancy loss and infertility.