Research
Basic Science: Obstetrics
A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells

Presented orally at the 30th Annual Meeting of the Society for Maternal-Fetal Medicine, Chicago, IL, Feb. 1-6, 2010.
https://doi.org/10.1016/j.ajog.2010.03.024Get rights and content

Objective

Preimplantation factor (PIF) is a novel, 15 amino acid peptide, secreted by viable embryos. This study aims to elucidate PIF's effects in human endometrial stromal cells (HESC) decidualized by estrogen and progestin, which mimics the preimplantation milieu, and in first-trimester decidua cultures (FTDC).

Study Design

HESC or FTDC were incubated with 100 nmol/L synthetic PIF or vehicle control. Global gene expression was analyzed using microarray and pathway analysis. Proteins were analyzed using quantitative mass spectrometry, and PIF binding by protein array.

Results

Gene and proteomic analysis demonstrate that PIF affects immune, adhesion, and apoptotic pathways. Significant up-regulation in HESC (fold change) include: nuclear factor-k-β activation via interleukin-1 receptor-associated kinase binding protein 1 (53); Toll-like receptor 5 (9); FK506 binding protein 15, 133kDa protein (2.3); and Down syndrome cell adhesion molecule like 1 (16). B-cell lymphoma protein 2 was down-regulated in HESC (21.1) and FTDC (27.1). Protein array demonstrates PIF interaction with intracellular targets insulin-degrading enzyme and beta-K+ channels.

Conclusion

PIF displays essential multitargeted effects, of regulating immunity, promoting embryo-decidual adhesion, and regulating adaptive apoptotic processes.

Section snippets

Peptide synthesis

Synthetic PIF analog (MVRIKPGSANKPSDD) was produced using solid-phase peptide synthesis (Peptide Synthesizer; Applied Biosystems, Foster City, CA) employing Fmoc (9-fluorenylmethoxycarbonyl) chemistry. Final purification was carried out by reversed-phase high-pressure liquid chromatography, and peptide identity was verified by mass spectrometry. Alexa Fluor 647-PIF conjugate was generated as well (Bio-Synthesis Inc, Lewisville, TX).

Endometrial cell cultures

Institutional review board approval was obtained for this

Effect of PIF on HESC

PIF 100 nmol/L significantly changed >500 genes. The genes that were significantly changed (>10-fold) are featured in Table 1. Notably, there was an 18.1-fold decrease in phosphodiesterase 4B, cyclic AMP-specific (phosphodiesterase, a gene encoding for a protein that specifically hydrolyzes cyclic AMP, a critical molecule promoting decidualization.32

We focused on 3 pathways that are relevant for implantation: (1) immune tolerance; (2) embryo adhesion; and (3) apoptosis/remodeling.

Immune pathway

PIF increased

Comment

In this study, we demonstrated that PIF affects implantation and postimplantation in decidual models. Complementary global genome and evaluable stringent proteome analysis demonstrate synergistic effects on immune, adhesion, and apoptotic/remodeling pathways in the periimplantation model (HESC) and similarly in early pregnancy (FTDC). PIF exerts more of an “adaptive” influence in FTDC by supporting protein synthesis and protecting against environmental insults.

To discern the relevance of our

Conclusion

PIF modulates, and possibly orchestrates, maternal immunity without deleterious immune suppression, prepares the local uterine environment for implantation, and creates a supportive environment for early pregnancy. Our genomic and proteomic data significantly advance understanding of PIF's essential multitargeted effects of regulating immunity, promoting embryo-decidual adhesion, and regulating adaptive apoptotic processes. Relevant putative intracellular PIF mechanistic targets were identified

Acknowledgment

The authors thank Mr Kevin Leitao for assistance in preparing the data for publication.

References (46)

  • S.J. Huang et al.

    Regulation of chemokine production in response to pro-inflammatory cytokines in first trimester decidual cells

    J Reprod Immunol

    (2006)
  • P. Matta et al.

    Thrombin regulates monocyte chemoattractant protein-1 expression in human first trimester and term decidual cells

    Am J Obstet Gynecol

    (2007)
  • C.J. Lockwood et al.

    Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells

    Am J Pathol

    (2008)
  • M.M. Abou-Jaoude et al.

    Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients

    Transplant Proc

    (2005)
  • N.G. Than et al.

    Embryo-placento-maternal interaction and biomarkers: from diagnosis to therapy–a workshop report

    Placenta

    (2007)
  • M.K. Sanyal et al.

    Augmentation of polynuclear aromatic hydrocarbon metabolism of human placental tissues of first-trimester pregnancy by cigarette smoke exposure

    Am J Obstet Gynecol

    (1993)
  • K.G. Chandy et al.

    Physiological role, molecular structure and evolutionary relationships of voltage-gated potassium channels in T lymphocytes

    Semin Neurosci

    (1993)
  • U. von Rango et al.

    Cytokine microenvironments in human first trimester decidua are dependent on trophoblast cells

    Fertil Steril

    (2003)
  • U. von Rango et al.

    Indoleamine-dioxygenase is expressed in human decidua at the time maternal tolerance is established

    Reprod Immunol

    (2007)
  • S.R. Choudhury et al.

    Human reproductive failure I: immunological factors

    Hum Reprod Update

    (2001)
  • J.D. Aplin et al.

    Trophoblast-uterine interaction at implantation

    Reprod Biol Endocrinol

    (2004)
  • N. Ledee et al.

    Uterine receptivity and cytokines: new concepts and new applications

    Gynecol Obstet Invest

    (2007)
  • G. Chaouat et al.

    TH1/TH2 paradigm in pregnancy: paradigm lost?Cytokines in pregnancy/early abortion re-examining the TH1 and TH2 paradigm

    Int Arch Allergy Immunol

    (2004)
  • Cited by (0)

    Cite this article as: Paidas MJ, Krikun G, Huang SJ, et al. A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells. Am J Obstet Gynecol 2010;202:459.e1-8.

    The racing flag logo above indicates that this article was rushed to press for the benefit of the scientific community.

    Dr Paidas received unrestricted research funding from BioIncept LLC. This work was supported by National Institutes of Health Grant 5R01HD056123-02 (to Dr Huang).

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