Inhibition of PIM1 kinase attenuates inflammation-induced pro-labour mediators in human foetal membranes in vitro

Mediators of Inflammation

2020

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Problem. Some G-protein-coupled receptors (GPCRs) are regulators of inflammation, yet the role of the GPRC, GPR91, is unknown in human myometrium during the processes of human labor and delivery, a major inflammatory event. Method of Study. GPR91 mRNA expression was assessed using RT-qPCR in myometrium obtained from women at term Caesarean section in the absence of labor and during active spontaneous labor and in a mouse model of inflammation-induced preterm labor. Human primary myometrial cells were used to determine the effect of proinflammatory mediators on GPR91 and the effect of GPR91 siRNA on prolabor mediators. Statistical significance was ascribed to a P<0.05. Results. GPR91 mRNA expression was significantly higher in myometrium from women during term spontaneous labor compared to no labor. Likewise, in mice, GPR91 mRNA expression was significantly upregulated in myometrium during inflammation-induced preterm labor compared to preterm no labor. In myometrial cells, IL1B and TNF significantly increased GPR91 mRNA expression. Knockdown of GPR91 by siRNA in myometrial cells significantly suppressed the secretion and/or expression of IL1B- and TNF-induced proinflammatory cytokines (GM-CSF, IL1A, IL1B, and IL6) and chemokines (CXCL8 and CCL2), myometrial contractility (expression of the contraction-associated proteins PTGFR and CX43, secretion of the uterotonic PGF2α, and in situ collagen gel contraction), and the transcription factor NF-κB. Conclusion. Our findings demonstrate that GPR91 is involved in the genesis of proinflammatory and prolabor mediators induced by IL1B or TNF and collectively suggest that GPR91 may contribute to augmentation of the labor processes.

Section: Methodsmentioning

confidence: 99%

Inhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium

Lim

Mediators of Inflammation

2020

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“…To characterize infection‐associated changes in Mincle expression, amnion was collected from women undergoing Caesarean section in the absence of labour (i) with histologically confirmed acute chorioamnionitis or (ii) without histologically confirmed acute chorioamnionitis ( n = 8 patients per group), as previously described . Also as previously described , choriodecidual tissue could not be collected from the samples with histologically confirmed acute chorioamnionitis, as it was degraded. The relevant clinical characteristics of the patients used for these studies are detailed in the Supporting information, Table S.…”

Section: Methodsmentioning

confidence: 99%

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Lim

Clinical and Experimental Immunology

2019

The pivotal role of inflammatory processes in human parturition is well known, but not completely understood. We have performed a study to examine the role of macrophage-inducible C-type lectin (Mincle) in inflammation-associated parturition. Using human samples, we show that spontaneous labour is associated with up-regulated Mincle expression in the myometrium and fetal membranes. Mincle expression was also increased in fetal membranes and myometrium in the presence of pro-labour mediators, the proinflammatory cytokines interleukin (IL)-1B and tumour necrosis factor (TNF), and Toll-like receptor (TLR) ligands fsl-1, poly(I:C), lipopolysaccharide (LPS) and flagellin. These clinical studies are supported by mouse studies, where an inflammatory challenge in a mouse model of preterm birth increased Mincle expression in the uterus. Importantly, elimination of Mincle decreased the effectiveness of proinflammatory cytokines and TLR ligands to induce the expression of pro-labour mediators; namely, proinflammatory cytokines and chemokines, contraction-associated proteins and prostaglandins, and extracellular matrix remodelling enzymes, matrix metalloproteinases. The data presented in this study suggest that Mincle is required when inflammatory activation precipitates parturition.

“…The relevant clinical characteristics of the patients used for Cohort 3 (preterm samples) are described in Table . The relevant clinical characteristics of the patients used for Cohort 4 (term samples) have previously been described …”

Section: Methodsmentioning

confidence: 99%

“…To characterize infection‐associated changes in the mRNA expression of MT1 isoforms, MT2A, MT3, and MT4, amnion was collected from women undergoing cesarean section in the absence of labor (a) with histologically confirmed acute chorioamnionitis or (b) without histologically confirmed acute chorioamnionitis (n = 8 patients per group). As previously detailed, choriodecidual tissue could not be collected from the samples with histologically confirmed acute chorioamnionitis as it was degraded. The relevant clinical characteristics of the patients used for this cohort have previously been described …”

Section: Methodsmentioning

confidence: 99%

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Expression and regulation of metallothioneins in myometrium and fetal membranes

2018

American J Rep Immunol

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