Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening

Abstract

1Cervical ripening is necessary for successful delivery. As cytokines are believed to be 2 involved in this process, the aim of this study was to investigate possible changes in the 3 mRNA and protein expression of pro-inflammatory (interleukin (IL)-1α, IL-1β, IL-12, IL-18) 4 and anti-inflammatory (IL-4, IL-10, IL-13) cytokines in the human cervix during pregnancy, 5 term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 6 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed 7 with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry 8 and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1α and IL-1β in the 9 laboring groups, while mRNA for IL-12 and IL-18 was downregulated (p<0.05). IL-4 mRNA 10 was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor 11 group than in the term labor group (p<0.05). The protein levels of IL-4 and IL-12 were lower 12 and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected 13 by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial 14 infection than in the non-infected group (p<0.05). IL-10 had higher expression in squamous 15 epithelium at preterm labor than at term (p<0.05). In conclusion, the major changes in pro-16 inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur 17 during the labor process irrespective of the length of gestation. However, our results indicate 18 that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in 19 the pathogenesis of preterm labor. 20 21

Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term

“…There is compelling evidence that physiologic parturition is associated with cellular and molecular signatures of inflammation in the chorioamniotic membranes [28,91–96], myometrium [18,20,22,23,25–27,30,93,96–102], and cervix [19,21,24,93,96,103–107]. Indeed, the participation of chemokines and pro-inflammatory cytokines [108–126], eicosanoids [99,127–137] and lipooxygenase arachidonate products [138–140] in physiologic labor is well established.…”

Progesterone Interactions with the Cervix: Translational Implications for Term and Preterm Birth

“…Although the results indicated more than 300 genes were differentially regulated between experimental groups, the authors concluded that, indeed, there were distinct molecular mechanisms between term and preterm cervical ripening. A more focused evaluation of cervical biopsy-derived pro- and anti-inflammatory cytokine expression in women [40] who were in preterm or term labor, not in labor, or not pregnant, concluded that there were differences between preterm labor related to infection versus noninfected and overall differences between term and preterm cervical cytokine expression pointed to anti-inflammatory cytokines as key actors.…”

“…Interestingly Dubicke et al found that rapid functional progesterone withdrawal by mifepristone treatment of mice upregulated Pgts1 (Cox 1) [40]. Also in pregnant mice, lipopolysaccharide induced prostaglandins (PGs) and nitric oxide (NO) in tandem and inhibitors diminished both PG and NO as well as birth [71].…”

miR-143 and miR-145 disrupt the cervical epithelial barrier through dysregulation of cell adhesion, apoptosis and proliferation

“…While the mechanisms regulating cervical remodeling remain largely unknown, there are many factors that may have the ability to alter the cervical epithelial barrier and, hence, initiate cervical remodeling including alterations in inflammation and infection 9, 15 , biomechanical properties of the cervix 16–18 , microRNAs (miRNAs) 19, 20 and the cervicovaginal microbiome 21 and metabolome 22 . In a previous study, we investigated the expression of miRNAs in a cohort of women at high risk for preterm birth 20 .…”