Uterine Epithelial Cells Specifically Induce Interferon-Stimulated Genes in Response to Polyinosinic-Polycytidylic Acid Independently of Estradiol

Interferon beta (IFN beta) is an antiviral cytokine secreted in response to pathogenic exposure that creates a restrictive intracellular environment through the action of downstream interferon-stimulated genes (ISG). The objective of this study was to examine the expression of IFN beta and ISG in both human uterine epithelial cells (UEC) and the ECC-1 uterine epithelial cell line and determine if expression changes with TLR stimulation and hormone exposure. Stimulation of primary uterine epithelial cells and ECC-1 cells with the TLR3 agonist poly (I: C) induced the mRNA expression of IFN beta, MxA, OAS2 and PKR. Other TLR agonists including imiquimod and CpG had no effect on either IFN beta or ISG expression. In contrast to ECC-1 cell responses which were slower, maximal IFNb upregulation in UEC occurred 3 hours post-stimulation and preceded the ISG response which peaked approximately 12 hours after poly (I: C) exposure. Unexpectedly, estradiol, either alone or prior to treatment with poly (I: C), had no effect on IFN beta or ISG expression. Blockade of the IFN receptor abrogated the upregulation of MxA, OAS2 and PKR. Furthermore, neutralizing antibodies against IFN beta partially inhibited the upregulation of all three ISG. Estradiol, directly and in the presence of poly (I: C) had no effect on IFN beta and ISG expression. These results indicate that uterine epithelial cells are important sentinels of the innate immune system and demonstrate that uterine epithelial cells are capable of mounting a rapid IFN-mediated antiviral response that is independent of estradiol and is therefore potentially sustained throughout the menstrual cycle to aid in the defense of the uterus against potential pathogens.