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Inflammatory mediators in the response to myometrial strain and the transition into labor
AuthorSalem, Christian D. C.
Cell and Molecular Pharmacology and Physiology
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Preterm birth is one of the most costly, negative pregnancy outcomes that affects all populations worldwide. While the mechanisms that drive the transition into labor are not fully known, abnormal uterine distension is implicated in preterm birth in twins and 10% of singleton pregnancies. In Chapter 2, we hypothesized that specific phosphorylation signaling events related to the strain induced response would be upregulated in a telomerized cell culture model of human uterine smooth muscle cells. The phospho-proteome of these model cells was elucidated by mass spectrometry after cells were subjected to mechanical strain. These changes led us to hypothesize that these signaling events in the myometrium would be associated with strain induced expression of transcripts related to proteins involved in the transition into labor. Pregnant human uterine smooth muscle cells were subjected to biaxial mechanical strain for 3, 8 and 24 hours and the transcriptome probed by RNAseq. We used qPCR to investigate if p38 MAPK activation increases IL-6 transcription, and if increased IL-6 exposure can affect the transcription of contractile associated proteins Cx43 and the oxytocin receptor. Mechanical strain led to the direct activation of ERK1/2, HSP27, and MYLC9, in addition to phosphorylation of PAK2, vimentin, DOCK1, PPP1R12A, and PTPN11. These results suggest a novel network reaction to mechanical stretch and reveal proteins that participate in the activation of contractile mechanisms leading to preterm labor. In addition, at 3 and 8 hours of strain we saw increased transcripts for cytokines IL6, IL8, IL1β and CCL2 which are inflammatory mediators involved in labor. We found increases in the contractile associated proteins: oxytocin receptor, connexin45, and AP-1 subunits at 3 and 8 hours of strain. Finally, p38 MAPK inhibition blocked transcription of IL-6 in strained myometrial cells and incubation with IL-6 increased Cx43 and oxytocin receptortranscripts suggesting a mechanism for mechanical strain to contribute to the initiation of labor.