Identification of Chemokines Associated with the Recruitment of Decidual Leukocytes in Human Labour: Potential Novel Targets for Preterm Labour

Abstract

Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…These results coincide with previous studies demonstrating that choriodecidual leukocytes express CAMs [16,39,40], cytokines [8,41,42], chemokines [16,34], and their receptors [16,34,43], enzymes [35,44,45], antimicrobial peptides [46], markers of activation [17,39,[47][48][49], and even hormone receptors [50] before and during the process of labor. Together, these findings demonstrate that the choriodecidual leukocytes are a rich source of inflammatory mediators that can participate in the proinflammatory milieu that accompanies the process of labor.…”

“…Collectively, these data suggest that the chorioamniotic membranes, and most likely the decidual stromal cells, recruit maternal circulating leukocytes into the choriodecidua prior to and during the process of labor. Following recruitment, the choriodecidual leukocytes expressed cell adhesion molecules (CAMs) [16,[31][32][33] and labor mediators including cytokines/chemokines [14][15][16]34] and matrix metalloproteinases (MMPs) [35]. All of which elicit cellmediated immune responses that participate in the process of labor [1,[36][37][38].…”

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

“…MIP-1α is produced by cytotrophoblasts in the placenta to recruit large quantities of monocytes and NK cells to the uterine decidua during pregnancy (47). Chemokines are also up-regulated, and systemic leukocytes demonstrate increased chemotactic responsiveness at parturition and perhaps before parturition as well (48,49). In prior studies, stimulation of NK cells from pregnant women with IL-12/IL-15 was not associated with increased levels of MIP-1α or MIP-1β (13,14).…”

Comparison of whole genome expression profile between preterm and full-term newborns

“…During our study, we detected several genes from these pathways, which were down regulated in the preterm group versus the term babies. The study of expression of different CC and CXC chemokines in choriodecidual and maternal blood was performed in groups of term not in labor (TNF), term in labor (TL), idiopathic preterm labor (PTL) and preterm labor associated with infection (PTLI) [14]. Among differentially expressed chemokines, all of the groups revealed significant up-regulation in the TL vs. TNL.…”