Pro-labour myometrial gene expression: are preterm labour and term labour the same?

Abstract

Preterm labour (PTL) is the most important cause of neonatal morbidity and mortality. While some causes have been identified, the mechanisms involved remain elusive. This study investigates whether term labour (TL) is an appropriate model for PTL by examining prolabour gene expression, using quantitative rtPCR, and protein synthesis, using Western analysis, in preterm and term myometrial samples obtained from the upper and lower uterine segments before and after the onset of labour. In the lower segment, the levels of prostaglandin H synthase type-2 (PGHS-2), interleukin-1b (IL-1b), IL-6 and IL-8 mRNA expression were significantly higher in TL compared with PTL samples. Compared with non-labour controls, the expression of IL-1b and IL-8 mRNA was increased in both PTL and TL samples and the expression of PGHS-2 and IL-6 mRNA was increased in TL samples only. In the upper segment, there were no differences between PTL and TL samples and the mRNA expression of PGHS-2 and IL-1b was increased in TL compared with term no labour samples. No effect of PTL or TL was seen on either oxytocin receptor or connexin-43 mRNA expression or protein levels. The multiple regression analysis and studies in primary cultures of uterine myocytes suggest that the inflammatory cytokines, IL-1b and tumour necrosis factor-a, are the most important regulators of PGHS-2 and IL-8. Our data show that preterm and term labouring myometrium are significantly different and that the most marked labour-induced changes in gene expression are in the lower segment. These changes may occur in response to the release of inflammatory cytokines by the labour-associated inflammatory infiltration. Reproduction (2008) 135 569-579

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

“…13 In parallel, upregulation of pro-inflammatory cytokines mRNA expression of Interleukin-1 b (IL-1b, IL-6, C-X-C motif ligand (CXCL) 8 and C-C motif ligand (CCL) 2 was observed in the myometrium of healthy labouring women. [14][15][16][17][18] Our recent data confirmed these findings and revealed a more extensive list of up-regulated cytokine and chemokine proteins (CXCL8, CXCL1, CCL2, CCL7, IL-9, IL-18, IL-1RN, tumor necrosis factor alpha (TNFa) and granulocyte colony-stimulating factor (G-CSF)) in healthy TL human myometrial tissue samples, while also detecting a higher number of macrophage and neutrophil infiltrate. 7,19 The trigger that elevates cytokines in the myometrium of healthy women during labour remains largely elusive.…”

Microvesicles of Women With Gestational Hypertension and Preeclampsia Affect Human Trophoblast Fate and Endothelial Function

“…The involvement of prostaglandins and proinflammatory cytokines 17 has been suggested as a potential mechanism. It is possible that the elevation in the apoptosis rate induced by potent GVC-MVs bearing significant amounts of concentrated inflammatory cytokines, as revealed in our study, contribute in part to early delivery observed in women with GVCs.…”

RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators

“…It induces basal and store-operated calcium entry in myometrial smooth muscle cells (Tribe et al 2003), thus directly enhancing their contractile potential. IL1B can also increase the production of pro-inflammatory cytokines and chemokines; promote the production of prostaglandins via PTGS2, mediators of uterine contractions; and matrix metalloproteinases (MMPs) which activate cervical ripening and foetal membrane rupture, events culminating in successful labour and delivery (Roh et al 2000, Bowen et al 2002, Keelan et al 2003, Lappas & Rice 2004, Christiaens et al 2008, Tattersall, et al 2008. The findings of this study demonstrate that RAF1 is involved in the genesis of pro-inflammatory and RAF1 and labour in myometrium pro-labour mediators induced by IL1B.…”

“…Human labour is associated with increased concentrations of IL1B in both gestational tissues and biological fluids (Elliott, et al 2001, Bowen et al 2002, Tattersall et al 2008, and intra-amniotic and/or systemic administration of IL1B to mice and monkeys induces preterm labour (Romero et al 1991, Romero & Tartakovsky 1992, Sadowsky et al 2006. IL1B is thought to contribute to the onset of labour by stimulating and potentiating uterine contractions.…”

“…TNF is another pro-inflammatory cytokine that plays a central role in the terminal effector pathways of human labour and deliver. TNF can amplify or initiate the process of parturition by further increasing cytokine production, increasing PTGS2-mediated prostaglandin synthesis and activating MMPs (Roh et al 2000, Bowen et al 2002, Keelan et al 2003, Lappas & Rice 2004, Christiaens et al 2008, Tattersall et al 2008. In addition, TNF can induce preterm labour in animal models (Sadowsky et al 2006).…”