Inflammatory Amplification: A Central Tenet of Uterine Transition for Labor

Abstract

In preparation for delivery, the uterus transitions from actively maintaining quiescence during pregnancy to an active parturient state. This transition occurs as a result of the accumulation of pro-inflammatory signals which are amplified by positive feedback interactions involving paracrine and autocrine signaling at the level of each intrauterine cell and tissue. The amplification events occur in parallel until they reach a certain threshold, ‘tipping the scale’ and contributing to processes of uterine activation and functional progesterone withdrawal. The described signaling interactions all occur upstream from the presentation of clinical labor symptoms. In this review, we will: 1) describe the different physiological processes involved in uterine transition for each intrauterine tissue; 2) compare and contrast the current models of labor initiation; 3) introduce innovative models for measuring paracrine inflammatory interactions; and 4) discuss the therapeutic value in identifying and targeting key players in this crucial event for preterm birth.

Social Isolation Stress Modulates Pregnancy Outcomes and the Inflammatory Profile of Rat Uterus

“…Social stressors in rodents were shown to affect neurobiological mechanisms implicated in depression, including the activation of proinflammatory cytokines, increased levels of GCs, and upregulation of CRH and its receptors [ 68 ]. The proinflammatory IL-1β and IL-6 cytokines are key mediators involved in the inflammatory events of parturition [ 69 ] and are commonly upregulated in sterile inflammation and intrauterine infection associated with PTB [ 6 , 70 ]. Moreover, the peptide hormone CRH plays a central role in regulating the maternal and fetal HPA axis [ 71 ] and exerts its actions by activating two types of receptors, CRHR1 and CRHR2 [ 72 ].…”

“…Moreover, the peptide hormone CRH plays a central role in regulating the maternal and fetal HPA axis [ 71 ] and exerts its actions by activating two types of receptors, CRHR1 and CRHR2 [ 72 ]. Intrauterine CRH and its receptors have crucial roles in parturition [ 72 , 73 ], and their interplay and synergistic effects with proinflammatory cytokines, prostaglandins, and uterine activation proteins regulate the uterus’ transition to a procontractile state [ 69 ].…”

“…Shorter gestational length in the SIS-exposed F0 animals correlated with high uterine Il1b mRNA expression levels. This observation is likely explained by the role IL-1β plays in orchestrating downstream signalling of prolabour mediators [ 69 ]. The Il1b mRNA expression and protein abundance were reduced in offspring of MG and TG lineages in line with a return to normal gestation lengths.…”

A Leukocyte Migration Assay Assists Understanding of Interleukin-1β-Induced Leukocyte Migration Into Preterm Mouse Uterus

“…The translational implications of this work are significant. Rytvela, our IL-1R allosteric inhibitor, is a formidable therapeutic candidate against PTB and the accompanying long-term physiological consequences on the offspring ( Nadeau-Vallee et al, 2017 ; Coler et al, 2021 ; Leimert et al, 2021 ). It selectively inhibits IL-1R signaling down the mitogen-activated protein kinase/p38 pathway that signals for the amplification of the inflammatory cascade that leads to parturition ( Nadeau-Vallee et al, 2015 ).…”

Decidualization and Related Pregnancy Complications

“…(3) The expressions of all PGR isoforms diminish; (4) Proinflammatory mediators such as IL-6, CCL2, CCL4, CCL5, CXCL8, and CXCL10 are upregulated in the decidua at term and correlate with decidual leukocyte abundance. 74 Notably, the senescence of the decidual tissue turned out to be essential for the initiation of labor. 75 Additionally, DSCs are heterogeneous at the transcriptomic level at different stages of pregnancy.…”