IL‐1β and IL‐8 in Human Fetal Membranes: Changes with Gestational Age, Labor, and Culture Conditions

Elliott, Catherine; Loudon, J. A. Z.; Brown, Naoko; Slater, Donna M.; Bennett, Phillip R.; Sullivan, Mark

doi:10.1034/j.1600-0897.2001.d01-11.x

Cited by 98 publications

(72 citation statements)

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“…Data on the effect of pharmacological HDAC inhibition on NF-B seem contradictory, with some studies showing a potentiation Adam et al, 2003;Yeung et al, 2004) and others reporting an inhibition (Lü hrs et al, 2002;Takada et al, 2006) of NF-B activity. Several studies using the same HDACi compound used very different treatment protocols, with exposure of cells to HDACi ranging from 1 to 24 h. IL-1␤ activates NF-B, it is considered a master regulator of inflammation in diverse disease processes, its expression increases in the uterus as term approaches and in association with labor onset (Elliott et al, 2001;Mendelson and Condon, 2005), and administration of IL-1␤ can induce labor in the rhesus monkey (Vadillo-Ortega et al, 2002). We therefore tested both long-and short-term effects of the HDACi TSA on IL-1␤-induced NF-B activity in human myometrial cells.…”

Section: Resultsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-κB but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells

Lindström

Mohan²,

Johnson³

et al. 2008

Mol Pharmacol

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Premature activation of the inflammatory processes that mediate human parturition leads to preterm birth, a major clinical problem associated with neonatal morbidity and mortality. Histone deacetylase inhibitors (HDACi) are currently in clinical trials for the treatment of inflammatory disorders. Recent evidence suggests that there may be a therapeutic use for HDACi in the management of preterm birth, with administration of HDACi to pregnant mice shown to delay delivery. Because NF-B is a key orchestrator of the inflammatory response and plays a pivotal role in parturition, it is important to understand how administration of HDACi might affect NF-B activity in human uterine tissues. We show here that the effects of HDACi on nuclear factor-B (NF-B) in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced interleukin (IL)-1␤-induced NF-B activity as a result of potentiating IB kinase (IKK)␤ activity, thereby leading to persistent turnover of IB␣/ proteins and prolonging NF-B phosphorylation, nuclear localization, and DNA binding. Conversely, longterm HDACi treatments resulted in repression of NF-B DNA binding. Nevertheless, both short-and long-term HDACi treatments inhibited the expression of four labor-associated proinflammatory genes (COX-2, IL-8, IL-6, and RANTES), and this was associated with repression of the proinflammatory transcription factor c-Jun. Together, our data indicate that HDACi exert anti-inflammatory effects in human myometrium and may thus be useful in achieving a myometrial gene expression profile that favors uterine quiescence. However, coadministration of an IKK␤ inhibitor may be both necessary and sufficient to circumvent potential induction of labor-associated pathways that could result from HDACi-induced augmentation of NF-B activity.During parturition, myometrium undergoes a transition from a state of quiescence to one of contractility, resulting in delivery of the neonate. Although the molecular mechanisms that underpin this transition are poorly understood, it is widely accepted that parturition is an inflammatory process, involving the up-regulation of multiple proinflammatory genes (Romero et al., 2006). Premature activation of uterine proinflammatory pathways can lead to preterm birth, a major clinical problem that occurs in 5 to 10% of pregnancies and is associated with 70 to 75% of neonatal morbidity/ mortality (Wen et al., 2004).Histone acetylation plays a major role in gene transcription, enabling the partial unraveling of local chromatin structure that is required to make the DNA accessible for binding by transcription factors and the basal transcription machinery (Li et al., 2004). Acetylation is reversible and reflects a dynamic balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant recruitment of HDACs to promoters and/or overexpression of HDACs are observed in cancer cells, and This work was supported by Tommy's Campaign. Article, publication date, and citation information can be foun...

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Section: Resultsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-κB but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells

Lindström

Mohan²,

Johnson³

et al. 2008

Mol Pharmacol

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“…Term labour is the result of physiological activation of this pathway, while preterm labour is due to pathological insults (Romero et al 2006). There appears to be a causal role for IL1b in the processes of parturition; there is elevated expression of IL1b in the third trimester during normal pregnancies without signs of infection (Elliott et al 2001) as well as in pregnancies that display infection and in preterm deliveries (Goldenberg et al 2000, Menon & Fortunato 2004, Farina & Winkelman 2005. Intrauterine infection caused by bacteria is a common and important mechanism that leads to preterm birth (Goldenberg et al 2000).…”

Section: Discussionmentioning

confidence: 99%

KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium

Lappas¹

2015

Reproduction

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The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFkB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1b), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1b, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1b-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE 2 and PGF 2a . KLF5 silencing also significantly reduced flagellin-and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1b-, flagellin-and poly(I:C)-stimulated NFkB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation-and infection-induced pro-labour mediators.

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“…The fact that decidual CD4 + T cells express IL-1β, TNF-α and MMP-9 (i.e. labor mediators [133][134][135][136][137][138][139][140][141][142]) during spontaneous labor at term [65], as well as activation markers such as CD25 [143], suggests that the adaptive limb of the immune system participates in the process of parturition.…”

Section: A Role For T Cells In Pregnancymentioning

confidence: 99%

Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: A marker of allograft rejection

Maymon

Romero

Bhatti

et al. 2018

Journal of Perinatal Medicine

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Objective: The objective of this study is to determine whether the amniotic fluid (AF) concentration of soluble CXCR3 and its ligands CXCL9 and CXCL10 changes in patients whose placentas show evidence of chronic chorioamnionitis or other placental lesions consistent with maternal anti-fetal rejection. Methods: This retrospective case-control study included 425 women with (1) preterm delivery (n = 92); (2) term in labor (n = 68); and (3) term not in labor (n = 265). Amniotic fluid CXCR3, CXCL9 and CXCL10 concentrations were determined by ELISA. Results: (1) Amniotic fluid concentrations of CXCR3 and its ligands CXCL9 and CXCL10 are higher in patients with preterm labor and maternal anti-fetal rejection lesions than in those without these lesions [CXCR3: preterm labor and delivery with maternal anti-fetal rejection placental lesions (median, 17.24 ng/mL; IQR, 6.79-26.68) vs. preterm labor and delivery without these placental lesions (median 8.79 ng/mL; IQR, 4.98-14.7; P = 0.028)]; (2) patients with preterm labor and chronic chorioamnionitis had higher AF concentrations of CXCL9 and CXCL10, but not CXCR3, than those without this lesion [CXCR3: preterm labor with chronic chorioamnionitis (median, 17.02 ng/mL; IQR, 5.57-26.68) vs. preterm labor without chronic chorioamnionitis (median, 10.37 ng/mL; IQR 5.01-17.81; P = 0.283)]; (3) patients with preterm labor had a significantly higher AF concentration of CXCR3 than those in labor at term regardless of the presence or absence of placental lesions. Conclusion: Our findings support a role for maternal antifetal rejection in a subset of patients with preterm labor.

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IL‐1β and IL‐8 in Human Fetal Membranes: Changes with Gestational Age, Labor, and Culture Conditions

Abstract: Increasing expression of IL-1beta and IL-8 in amnion and choriodecidua in the third trimester and after labor supports a role for these cytokines in the establishment of labor.

Cited by 98 publications

References 0 publications

Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-κB but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells

Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-κB but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells

KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium

Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: A marker of allograft rejection

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