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Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia

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Abstract

C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant numbers and/or activation of these decidual immune cells elicit preeclampsia development. Decidual macrophages and NK cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester decidual cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56bright CD16− NK cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and decidual cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56bright CD16− NK cell migration. In conclusion, the current study suggests that decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

    S. Joseph Huang MD, PhD, Ya-Chun Yu MS & Chun-Yen Huang PhD

  2. Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd. MDC48, Tampa, FL, 33612, USA

    S. Joseph Huang MD, PhD, Frederick Schatz PhD & Charles J. Lockwood MD, MHCM

  3. Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan

    Chie-Pein Chen MD, PhD

  4. Clinical Research Support Lab, Yale Cancer Center, New Haven, CT, USA

    Lynn Buchwalder MS

  5. Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    Longzhu Piao PhD

Authors
  1. S. Joseph Huang MD, PhD
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  2. Chie-Pein Chen MD, PhD
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  3. Lynn Buchwalder MS
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  4. Ya-Chun Yu MS
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  7. Frederick Schatz PhD
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  8. Charles J. Lockwood MD, MHCM
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Correspondence to S. Joseph Huang MD, PhD.

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Huang, S.J., Chen, CP., Buchwalder, L. et al. Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia. Reprod. Sci. 26, 1256–1265 (2019). https://doi.org/10.1177/1933719118815592

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