Hi everyone, my name is Emily McKinney and welcome to my presentation on the role of oxytocin and the oxytocin receptor on the paracrine control of human parturition. I'd like to start my presentation with some background on oxytocin. It's a neuropeptide hormone implicated in many processes throughout the body, most notably within the reproductive system. It's widely used clinically as a medication to induce and augment labor and manage postpartum hemorrhage. The oxytocin and receptor system has been well studied within the myometrium surrounding labor. However, its role within the labor-associated inflammatory response at the maternal-fetal interface has yet to be studied. Our hypothesis is that this oxytocin and oxytocin receptor complex has an immunomodulatory effect on the decidual cells at parturition. On the screen here, you can see a schematic of our maternal-fetal interface anatomy with the amnion, chorion, and decidual cells. The direct contact between the fetal and maternal cells gives a unique mixture of decidualized stromal cells and maternal immune cells depicted by those green circles. This is a unique target for immunomodulation that occurs at labor and is an especially interesting area for research. For our methods, we collected fetal membranes from term, C-section, and vaginal deliveries categorized as clinically in labor or not in labor. X-plant culture was performed on C-section tissues. You can see how we performed these X-plants from the schematic below. With this sheet of fetal membranes, we cut up and put into these petri dishes. We then treated each row or column with different treatment modalities, and then we performed parallel experiments with an immortalized human decidual stromal cell line known as IDAC cells. All of this RNA was extracted, and we performed qPCR to measure the relative abundance of mRNA encoding for oxytocin receptor and IL-8, and then we performed statistical analysis on all of this. Looking at our results, at our first graph here, you can see that in term-laboring MFI tissue, the relative abundance of mRNA coding for the oxytocin receptor in the decidua increased in association with the onset of labor. In our 18 in-labor patients, there was a significant increase in the expression of the oxytocin receptor. Moving on to our inflammation and oxytocin receptor expression, treating with an inflammatory stimulus, IL-1 beta increased OXTR gene expression in our MFI X-plants. Then if we look directly below, you can see that in IDAC cells, IL-1 beta, our inflammatory stimulus also increased OXTR expression in a concentration-dependent manner. Interestingly, our most exciting experiment, in my opinion, was when we decided to treat with oxytocin and measure IL-8 as a measure of inflammation. We found that oxytocin inhibited IL-1 beta-induced expression of IL-8. When we found the increase in IL-8 expression with IL-1 beta-treated X-plants, that followed our consistent data from above. Then when we treated with oxytocin, we found a decrease in inflammation, and then treating with both oxytocin and that inflammatory stimulus proved that our oxytocin was anti-inflammatory, which was quite interesting. Concluding all of our thoughts here, the onset of labor was known to be associated with inflammation at the maternal-fetal interface, so this increase in oxytocin receptor expression makes sense comparing in-term labor to not-in-term labor. Additionally, the inflammatory stimulus IL-1 beta increasing the relative abundance of mRNA encoding for oxytocin receptor in the X-plants and IDAC cells makes sense as well considering we need to recruit oxytocin receptors at the time of labor to enhance the oxytocin response in the localized area of the uterus. Interestingly, oxytocin had a potent anti-inflammatory effect at the maternal-fetal interface, and this was modeled by our inhibition of IL-1 beta-induced IL-8 expression. In general, this balance of the oxytocin-oxytocin receptor complex at the fetal membranes is incredibly fascinating as an area for future research to better understand this mechanism of fetal membrane quiescence during pregnancy and how these membranes stay in this perfect balance right up until partituration, and especially considering the clinical applications for labor induction and postpartum hemorrhage management, this is a really fascinating area for future research. Please let me know if you have any questions, and thank you so much for listening to my presentation. I'd like to give a special shout-out to Case Western Reserve, University Hospitals, and the Messianna Lab for all of their help and support with this project. Thank you so much!

oxytocin

parturition

immunomodulatory

inflammation

pregnancy