Progesterone, the maternal immune system and the onset of parturition in the mouse†

Abstract

The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2), and the onset of parturition was examined in (i) naïve mice delivering at term; (ii) E16 mice treated with RU486 (P4-antagonist) to induce preterm parturition; and (iii) in mice treated with P4 to prevent term parturition. In naïve mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43, and COX-2 increased with, but not before, parturition. With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9 h post-RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition. In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented, and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation, myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased. These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabor factor synthesis via mRNA-dependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation.

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

“…The total number of circulating natural killer cells and secretion of pro-inflammatory cytokines (IFN-gamma) is also reduced in the pregnant state (Veenstra Van Nieuwenhoven et al, 2002 ). However, close to parturition, the maternal immune system shifts to a pro-inflammatory state, particularly locally within the uterus, to promote labor (Mor and Cardenas, 2010 ; Edey et al, 2018 ). There are also specific changes in the numbers of different leukocyte populations in the maternal thymus and spleen during pregnancy (Clarke and Kendall, 1994 ; Kendall and Clarke, 2000 ; Norton et al, 2009 ).…”

Regulation of p38 mitogen‐activated kinase‐mediated fetal membrane senescence by statins

“…22 Simvastatin has previously been shown by our group to minimize infection-associated inflammation. 36,37 Progesterone is a vital hormone for the continuum of pregnancy. 30 It has been studied in various inflammatory conditions such as rheumatoid arthritis, 31 asthma, 32 and stroke 33 where it has shown to reduce the expression of proinflammatory cytokines and chemokines.…”

“…34,35 Similarly, progesterone is a well-reported anti-inflammatory agent. 36,37 Progesterone is a vital hormone for the continuum of pregnancy. 38 Although not successful, both 17-hydroxy progesterone caproate and vaginal administration of progesterone have been used extensively in an attempt to minimize the risk of PTB.…”

Systematic review of p38 mitogen‐activated kinase and its functional role in reproductive tissues

“…Recently, we reported that activation of the p38 MAPK pathway by oxidative stress in human fetal membrane tissues causes cellular senescence and sterile inflammation, which are postulated to trigger parturition . Animal model studies have also confirmed its potential role in the initiation of labor . However, it is premature to state that p38 MAPK is the key mediator of parturition based on its activation in chorioamniotic membranes to various stimuli.…”