Monocyte Chemoattractant Protein-1 (CCL-2) Integrates Mechanical and Endocrine Signals That Mediate Term and Preterm Labor

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(2):1470-9. DOI: 10.4049/jimmunol.181.2.1470
Source: PubMed


Recent evidence suggests that leukocytes infiltrate uterine tissues at or around the time of parturition, implicating inflammation as a key mechanism of human labor. MCP-1 (also known as C-C chemokine motif ligand 2, CCL-2) is a proinflammatory cytokine that is up-regulated in human myometrium during labor. Myometrium was collected from pregnant rats across gestation and at labor. Total RNA and proteins were subjected to real-time PCR and ELISA, respectively. Ccl-2 gene and protein expression was significantly up-regulated in the gravid rat myometrium before and during labor, which might suggest that it is regulated positively by mechanical stretch of the uterus imposed by the growing fetus and negatively by physiological withdrawal of progesterone (P4). We confirmed in vivo that: 1) administration of P4 receptor antagonist RU486 induced an increase in Ccl-2 mRNA and preterm labor, whereas 2) artificial maintenance of elevated P4 levels at late gestation caused a significant decrease in gene expression and blocked labor; 3) Ccl-2 was elevated specifically in the gravid horn of unilaterally pregnant rats suggesting that mechanical strain imposed by the growing fetus controls its expression in the myometrium; 4) in vitro static mechanical stretch of primary rat myometrial smooth muscle cells (25% elongation) induced a release of Ccl-2 protein, which was repressed by pretreatment with P4 (1 microM); and 5) stretch enhanced their monocyte chemoattractant activity. These data indicate that Ccl-2 protein serves to integrate mechanical and endocrine signals contributing to uterine inflammation and the induction of labor and thus may represent a novel target for therapeutic prevention of preterm labor in humans.

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Available from: Oksana Shynlova
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    • "Furthermore, MCP-1 expression and macrophage infiltration were greatly increased in the pregnant rat uterus after PR blockade by RU486 treatment, which caused preterm parturition. MCP-1 and macrophage infiltration were inhibited by progestin treatment , which delayed parturition (Shynlova et al. 2008). Using telomerase-immortalized human myometrial cells, P 4 /PR was found to serve a major anti-inflammatory role via antagonism of both NF-kB activation and COX-2 expression (Havelock et al. 2005; Hardy and Mendelson 2006). "
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    ABSTRACT: The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called "contractile" genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Full-text · Article · Sep 2015 · Cold Spring Harbor Perspectives in Medicine
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    • "Therefore, it is likely that paracrine factors such as cytokines and chemokines act as effectors of steroid hormones, thus enabling systemic immune modulation in the absence of leukocyte steroid receptors. In fact, there is ample evidence in the literature for regulation of immune function by progesterone through its effect on smooth muscle, stromal, and perivascular cells (Gotkin et al., 2006; Hardy et al., 2006; Luk et al., 2010; Shields et al., 2005; Shynlova et al., 2008). Due to its multiple cellular targets, a comprehensive dissection of cell specific signaling, as well as direct downstream targets of PR, is necessary to understand the multiple immune-modulatory functions of progesterone. "
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    ABSTRACT: Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues.
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    • "Considering our previous reports which demonstrated stromal contacts between TCs and immune cells (eosinophils, macrophages and plasma cells) in rat myometrium (Popescu et al. 2005b), we can hypothesise a role in immune surveillance. Leucocytes are known to be crucial for pregnancy maintenance and for the mechanism of uterine activation during labour (Thomson et al. 1999, Keski-Nisula et al. 2003, Shynlova et al. 2008). In our opinion TCs, myocytes and leucocytes could work together in pregnancy maintenance or in the onset of labour. "
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    ABSTRACT: Telocytes (TCs) have been described in various organs and species ( as cells with telopodes (Tps) — very long cellular extensions with an alternation of thin segments (podomers) and dilated portions (podoms). We examined TCs using electron microscopy (EM), immunohistochemistry (IHC), immunofluorescence (IF), time-lapse videomicroscopy and whole-cell patch voltage-clamp. EM showed a three-dimensional network of dichotomous-branching Tps, a labyrinthine system with homo- and hetero-cellular junctions. Tps release extracellular vesicles (mean diameter of 160.6±6.9 nm in non-pregnant myometrium and 171.6±4.6 nm in pregnant myometrium), sending macromolecular signals to neighbouring cells. Comparative measurements (non-pregnant and pregnant myometrium) of podomer thickness revealed values of 81.94±1.77 nm vs. 75.53±1.81 nm, while the podoms diameters were 268.6±8.27 nm vs. 316.38±17.56 nm. IHC as well as IF revealed double c-kit and CD34 positive results. Time-lapse videomicroscopy of cell culture showed dynamic interactions between Tps and myocytes. In non-pregnant myometrium, patch-clamp recordings of TCs revealed a hyperpolarization-activated chloride inward current with calcium dependence and the absence of L-type calcium channels. TCs seems to have no excitable properties as the surrounding smooth muscle cells. In conclusion, this study shows the presence of TCs as a distinct cell type in human non-pregnant and pregnant myometrium and describes morphometric differences between the two physiological states. In addition, we provide a preliminary in vitro electrophysiological evaluation of the non-pregnant state suggesting that TCs could influence timing of the contractile activity of smooth muscle cells.
    Full-text · Article · Feb 2013 · Reproduction (Cambridge, England)
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