Article

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: 5.36). 08/2008; 181(2):1470-9. DOI: 10.4049/jimmunol.181.2.1470
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Oksana Shynlova, Aug 20, 2015
0 Followers
 · 
113 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Vascular Pharmacology 06/2013; 59(1-2). DOI:10.1016/j.vph.2013.06.001 · 4.62 Impact Factor
  • Source
    • "Progesterone itself inhibits IL-6 production in fetoplacental arteries (Gotkin et al., 2006), and progestogens such as medroxyprogesterone acetate inhibit a range of proinflammatory cytokines and chemokines in human myometrium (Shynlova et al., 2008, Youssef et al., 2009). Of particular interest are the interactions of progesterone with NF-κB, a transcription factor which has key functions within human parturition (Allport et al., 2001, Elliott et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human parturition is an inflammatory event, modulated and influenced by a host of other environmental and physiological processes, including the endocrine hormones. Complex bidirectional communication occurs between the two systems to bring about some of the changes that are seen in labour, an event that is not yet fully understood. Preterm birth is a major problem in obstetrics and neonatology, with dysfunctional labour or prolonged pregnancy also making increasingly significant contributions to maternal morbidity. With better understanding of normal and abnormal parturition we may be able to develop novel ways of treating these complications of pregnancy and reduce maternal and neonatal morbidity and mortality. This review discusses the crucial role that endocrine-immune interaction plays in the process of labour and in the processes of abnormal and preterm labour. We propose that amongst these complex interactions it is the immune system that is the driving force behind human parturition.
    Molecular and Cellular Endocrinology 03/2011; 335(1):52-9. DOI:10.1016/j.mce.2010.08.005 · 4.24 Impact Factor
  • Source
    • "physiological rise in mouse myometrial CCL2 in vivo (Shynlova et al. 2008). Although there has been little measurement of anti-inflammatory pathways in preterm pathological parturition, it is tempting to speculate that upregulation thereof could be a useful therapeutic strategy to prevent preterm delivery. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation involves alterations to vascular and immune cell function. It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. These are orchestrated by specific molecular pathways involving a host of growth factors, cytokines, chemokines and lipid mediators. Resumption of normal reproductive function involves prompt and proper resolution of these inflammatory pathways. Recent literature confirms that resolution of inflammatory pathways involves specific biochemical events that are activated to re-establish homeostasis in the affected tissue. Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution. This review will address the role of inflammatory events in normal reproductive function and its pathologies.
    Reproduction 09/2009; 138(6):903-19. DOI:10.1530/REP-09-0247
Show more