Intrauterine cooperativity: amplification between ligands, cells, and tissues to transition the uterus for parturition

• Author / Creator

  Leimert, Kelycia

• Birth is a complex biological event requiring genetic, cellular and physiological changes to the uterus, resulting in a uterus activated for completing the physiological processes of labour.
  We define the change from the state of pregnancy to the state of parturition as uterine transitioning, which requires the actions of inflammatory mediators and localized paracrine interactions between intrauterine tissues. In the human, the birth cascade involves positive feedback interactions between a series of parallel events integrating both pro-inflammatory and
  pro-contractile systems, which accumulate until reaching a ‘critical mass’ or threshold that triggers a labouring state. An activated uterus is marked by increased expression of uterine
  activation proteins (UAPs) resulting in the increased sensitivity of the myometrium to coordinated contraction. In addition to the actions of steroid hormones, key inflammatory mediators, IL-1β and PGF2α, regulate the expression of critical uterine activation proteins (UAPs) FP and COX2 and pro-inflammatory cytokines and chemokines in cultured primary human myometrium smooth muscle cells (HMSMC). We found that in addition to regulation of
  the PGF2α receptor FP, IL-1β and PGF2α also upregulate the IL-1 receptor system, including IL1R1, IL1R2, IL1RAcP and IL1RAcPBb. HMSMC treated with IL-1β then PGF2α (or vice versa) produce amplified increases in IL-6 and COX-2 mRNA and protein compared to treatment with either agonist alone. These large increases were unique to myometrium and not observed with hFM.

  Uterine transition not only comprises interactions between different inflammatory pathways, but also paracrine interactions between neighbouring cells and tissues. Few studies have examined the in vitro interactions between fetal and maternal gestational tissues within this pro-inflammatory environment. Thus we designed a co-culture model to address this gap,
  incorporating primary term human myometrium smooth muscle cells (HMSMC) with human fetal membrane (hFM) explants to study interactions between the tissues. We hypothesized that
  crosstalk between tissues at term promotes pro-inflammatory expression and uterine transitioning for parturition. Outputs of 40 cytokines and chemokines encompassing a variety of pro-inflammatory roles were measured; all but one increased significantly with co-culture. Eighteen of the 39 cytokines increased to a higher abundance than the sum of the effect of each tissue cultured separately. In addition, COX2 and IL6, but not FP and OTR mRNA abundance significantly increased in both HMSMC and hFM in response to co-culture. These data suggest
  that synergistic pro-inflammatory upregulation within intrauterine tissues is involved with uterine transitioning.

  The series of experiments described in this dissertation together present cooperativity between ligands, cells and tissues as a hallmark of human parturition. Our work establishes
  PGF2α and IL-1β as key triggers or upstream drivers of this process and IL-6 and COX-2 as key targets, promoting inflammatory amplification in the myometrium through positive feedback and synergy. We surmise that, if similar events occur in vivo, this large increase in mediators could reflect a critical event in the transition of the uterus from the state of pregnancy to the state of parturition.

• Subjects / Keywords

  • intrauterine cooperativity
  • uterus
  • amplification
  • inflammation
  • parturition
  • uterine transition

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3P26QK3S

• License

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