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.

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Available from: Oksana Shynlova, Aug 20, 2015
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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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    • "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). "
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    • "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. "
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