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Peripheral maternal leukocytes are activated in response to cytokines secreted by uterine tissues of pregnant women

Cellular & Molecular Immunology volume 14, pages 635–638 (2017)Cite this article

The infiltration of leukocytes into uterine tissue is an essential step in parturition. This phenomenon, described as physiologic sterile inflammation, has been demonstrated over the past decade through the observation of multiple leukocyte subpopulations (monocytes, granulocytes and lymphocytes) migrating into various reproductive tissues such as the cervix, decidua, myometrium and fetal membranes both prior to and during human labor.1, 2, 3 This mechanism is initiated by an increase in the secretion of pro-inflammatory cytokines and chemokines (signaling molecules responsible for immune cell activation and migration) by the uterine tissues and fetal membranes.3, 4, 5 Cytokines activate both endothelial cells in the local uterine vasculature (by upregulating cell adhesion molecules, such as ICAM1 and VCAM1) and circulating peripheral maternal leukocytes (by upregulating specific extracellular matrix receptors, such as CD11b and CD44), which facilitate the transendothelial migration of immune cells into the target uterine tissues.6 Once the leukocytes infiltrate the uterus, the inflammatory signal is amplified by these activated immune cells through prostaglandin production, which induces myometrial contractility;7 matrix metalloproteinase synthesis, which initiates membrane degradation and cervix ripening;8, 9 and by additional cytokine production, which results in the onset of term labor. Unfortunately, in 10% of all pregnancies, the same events are triggered early, with cytokine expression and leukocyte infiltration occurring prematurely (<37 weeks of gestation), resulting in preterm birth (PTB) of the immature neonate.10 PTB is a critical public health problem with high morbidity, mortality and health care costs.11 There are multiple triggers of PTB, with infection and multiple gestations being the most commonly recognized risk factors.12 Numerous studies have been undertaken to elucidate the specific molecular events responsible for labor initiation at term to predict targets for drug development and novel therapies that would prevent PTB in high-risk pregnant women.

Previously, we explored the effects of mechanical stretching on the myometrium by modeling the physiologic distention of the uterine walls by the growing fetus(es) using an in vitro model, the immortalized human myometrial cell line hTERT-HM in combination with the Flexcell stretch system.13 The effect of stretching on the myometrium was measured by examining four consecutive events involved in human labor: (1) cytokine expression by the myometrium, (2) activation of uterine endothelial cells, (3) peripheral leukocyte activation and (4) transendothelial migration of activated immune cells. We found that the static mechanical stretching of hTERT-HM cells for 24 h significantly increased the expression of nine cytokines (IL-6, IL-12p70, IL-8, GROa, MIF, G-CSF, bFGF, VEGF and PDGF-bb) that are involved in leukocyte activation, migration and biosynthesis compared to non-stretched cells. Conditioned media collected from stretched myometrial cells, which contained all the secreted cytokines and chemokines, activated uterine endothelial cells by significantly upregulating gene and protein levels of cell adhesion molecules (E-selectin, ICAM1 and VCAM1) on their surface compared with the effect of media conditioned by non-stretched cells. Following endothelial cell activation, we explored peripheral leukocyte activation by stretch-induced myometrial cytokines. Conditioned media from stretched and non-stretched myometrial cells elicited a significant upregulation of the activation markers CD11b (integrin αM) and CD44 (hyaluronic acid receptor) on the surface of human monocytes (THP-1 cell line) and primary human granulocytes, suggesting that leukocyte activation is stretch-independent. Finally, stretch-conditioned media significantly increased granulocyte adhesion to uterine endothelial cells and the transendothelial migration of primary granulocytes and monocyte THP-1 cells compared with media conditioned by non-stretched myometrial cells.

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Acknowledgements

This work was supported by a grant from Burroughs Wellcome Fund (grant #1013759). We are grateful to Mrs Anna Dorogin for her assistance in processing uterine tissues, Dr Caroline Dunk for her assistance with decidual cultures and Dr Jianhong Zhang for his assistance with flow cytometry. We thank obstetricians and nurses at Mount Sinai Hospital, Toronto, for helping with tissue collection and the LTRI Biobank for helping with blood collection.

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Authors and Affiliations

  1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Ontario, Canada

    Tali Farine, Stephen Lye & Oksana Shynlova

  2. Department of Physiology, University of Toronto, Toronto, M5S 1A1, Ontario, Canada

    Tali Farine & Stephen Lye

  3. Department of Obstetrics & Gynecology, University of Toronto, M5S 1A1, Ontario, Canada.

    Stephen Lye & Oksana Shynlova

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  1. Tali Farine
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Correspondence to Oksana Shynlova.

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Farine, T., Lye, S. & Shynlova, O. Peripheral maternal leukocytes are activated in response to cytokines secreted by uterine tissues of pregnant women. Cell Mol Immunol 14, 635–638 (2017). https://doi.org/10.1038/cmi.2017.29

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