Skip to main content
Log in

Programming of Human Monocytes by the Uteroplacental Environment

  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

During human pregnancy, monocytes recruited to the uterus (decidua) are modified to promote immune defense and semiallogeneic pregnancy. The purpose of this study was to identify decidual factors involved in programming of monocytes into decidual macrophages by comparing the surface and secretory phenotypes of resting and interferon-γ (IFN-γ)—activated monocytes, unfractionated decidual cells, purified term decidual macrophages, and monocyte-derived macrophages. Surface markers for antigen presentation (HLA-DR, CD86), a membrane-bound cytokine interleukin (IL)—15, leukocyte immunoglobulin-like receptors (LILRB1, LILRB2), and secreted anti-inflammatory cytokines (transforming growth factor [TGF]—β1 and IL-10) were assessed. The results demonstrate that differentiated, activated monocytes closely resemble but are not identical to decidual macrophages. In addition to differential IFN- γ responsiveness, decidual macrophages were smaller than monocyte-derived macrophages and produced IL-10, which monocyte-derived macrophages did not. Only the unfractionated decidual cells secreted TGF-β1. These results suggest that activation, differentiation, and decidual signals cooperate to program monocytes into the decidual macrophage phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.

    Article  CAS  PubMed  Google Scholar 

  2. Rutherford MS, Witsell A, Schook LB. Mechanisms generating functionally heterogeneous macrophages: chaos revisited. J Leukoc Biol. 1993;53:602–618.

    Article  CAS  PubMed  Google Scholar 

  3. Vince GS, Johnson PM. Immunobiology of human uteroplacental macrophages-friend and foe? Placenta. 1996;17:191–199.

    Article  CAS  PubMed  Google Scholar 

  4. Mor G, Abrahams VM. Potential role of macrophages as immunoregulators of pregnancy. Reprod Biol Endocrinol. 2003; 1:119.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hunt JS, Pollard JW. Macrophages in the uterus and placenta. Curr Top Microbiol Immunol. 1992;181:39–63.

    CAS  PubMed  Google Scholar 

  6. Nehemiah JL, Schnitzer JA, Schulman H, Novikoff AB. Human chorionic trophoblasts, decidual cells, and macrophages: a histochemical and electron microscopic study. Am J Obstet Gynecol. 1981;140:261–268.

    Article  CAS  PubMed  Google Scholar 

  7. Bulmer JN, Smith J, Morrison L, Wells M. Maternal and fetal cellular relationships in the human placental basal plate. Placenta. 1988;9:237–246.

    Article  CAS  PubMed  Google Scholar 

  8. Reister F, Frank HG, Kingdom JC, et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Invest. 2001;81:1143–1152.

    Article  CAS  PubMed  Google Scholar 

  9. Dorman PJ, Searle RF. Alloantigen presenting capacity of human decidual tissue. J Reprod Immunol. 1988;13:101–112.

    Article  CAS  PubMed  Google Scholar 

  10. Mizuno M, Aoki K, Kimbara T. Functions of macrophages in human decidual tissue in early pregnancy. Am J Reprod Immunol. 1994;31:180–188.

    Article  CAS  PubMed  Google Scholar 

  11. Verma S, Hiby SE, Loke YW, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Reprod. 2000;62:959–968.

    Article  CAS  PubMed  Google Scholar 

  12. Heikkinen J, Mottonen M, Komi J, Alanen A, Lassila O. Phenotypic characterization of human decidual macrophages. Clin Exp Immunol. 2003;131:498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Narahara H, Johnston JM. Effects of endotoxins and cytokines on the secretion of platelet-activating factoracetylhydrolase by human decidual macrophages. Am J Obstet Gynecol. 1993;169:531–537.

    Article  CAS  PubMed  Google Scholar 

  14. Arcuri F, Ricci C, Ietta F, et al. Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy. Biol Reprod. 2001;64:1200–1205.

    Article  CAS  PubMed  Google Scholar 

  15. Bowen JM, Chamley L, Mitchell MD, Keelan JA. Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta. 2002;23:239–256.

    Article  CAS  PubMed  Google Scholar 

  16. Bowen JM, Chamley L, Keelan JA, Mitchell MD. Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition. Placenta. 2002;23:257–273.

    Article  CAS  PubMed  Google Scholar 

  17. Lockwood CJ, Matta P, Krikun G, et al. Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia. Am J Pathol. 2006;168:445–452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arcuri F, Buchwalder L, Toti P, et al. Differential regulation of colony stimulating factor 1 and macrophage migration inhibitory factor expression by inflammatory cytokines in term human decidua: implications for macrophage trafficking at the fetal-maternal interface. Biol Reprod. 2007;76:433–439.

    Article  CAS  PubMed  Google Scholar 

  19. Veith GL, Rice GE. Interferon gamma expression during human pregnancy and in association with labour. Gynecol Obstet Invest. 1999;48:163–167.

    Article  CAS  PubMed  Google Scholar 

  20. Platt JS, Hunt JS. Interferon-gamma gene expression in cycling and pregnant mouse uterus: temporal aspects and cellular localization. J Leukoc Biol. 1998;64:393–400.

    Article  CAS  PubMed  Google Scholar 

  21. Xie X, He H, Colonna M, Seya T, Takai T, Croy BA. Pathways participating in activation of mouse uterine natural killer cells during pregnancy. Biol Reprod. 2005;73:510–518.

    Article  CAS  PubMed  Google Scholar 

  22. Bulmer JN, Pace D, Ritson A. Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function. Reprod Nutr Dev. 1988;28:1599–1613.

    Article  CAS  PubMed  Google Scholar 

  23. Lessin DL, Hunt JS, King CR, Wood GW. Antigen expression by cells near the maternal-fetal interface. Am J Reprod Immunol Microbiol. 1988;16:1–7.

    Article  CAS  PubMed  Google Scholar 

  24. Pollard JW. Role of colony-stimulating factor-1 in reproduction and development. Mol Reprod Dev. 1997;46:54–60.

    Article  CAS  PubMed  Google Scholar 

  25. Daiter E, Pampfer S, Yeung YG, Barad D, Stanley ER, Pollard JW. Expression of colony-stimulating factor-1 in the human uterus and placenta. J Clin Endocrinol Metab. 1992;74:850–858.

    Article  CAS  PubMed  Google Scholar 

  26. Pampfer S, Daiter E, Barad D, Pollard JW. Expression of the colony-stimulating factor-1 receptor (c-fms proto-oncogene product) in the human uterus and placenta. Biol Reprod. 1992; 46:48–57.

    Article  CAS  PubMed  Google Scholar 

  27. McIntire RH, Petroff MG, Phillips TA, Hunt JS. In vitro models for studying human uterine and placental macrophages. Methods Mol Med. 2006;122:123–148.

    PubMed  Google Scholar 

  28. Vince GS, Starkey PM, Jackson MC, Sargent IL, Redman CW. Flow cytometric characterisation of cell populations in human pregnancy decidua and isolation of decidual macrophages. J Immunol Methods. 1990;132:181–189.

    Article  CAS  PubMed  Google Scholar 

  29. Roby KF, Hamlin GP, Soares MJ, Hunt JS. Differential responses of phenotypically distinct rat trophoblast cell lines to MHC class I antigen-inducing cytokines. Placenta. 1994;15:577–590.

    Article  CAS  PubMed  Google Scholar 

  30. Lobo SC, Huang ST, Germeyer A, et al. The immune environment in human endometrium during the window of implantation. Am J Reprod Immunol. 2004;52:244–251.

    Article  PubMed  Google Scholar 

  31. Okada S, Okada H, Sanezumi M, Nakajima T, Yasuda K, Kanzaki H. Expression of interleukin-15 in human endometrium and decidua. Mol Hum Reprod. 2000;6:75–80.

    Article  CAS  PubMed  Google Scholar 

  32. Musso T, Calosso L, Zucca M, et al. Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15. Blood. 1999;93: 3531–3539.

    CAS  PubMed  Google Scholar 

  33. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J. 2005;19:681–693.

    Article  CAS  PubMed  Google Scholar 

  34. Petroff MG, Sedlmayr P, Azzola D, Hunt JS. Decidual macrophages are potentially susceptible to inhibition by class Ia and class Ib HLA molecules. J Reprod Immunol. 2002;56:3–17.

    Article  CAS  PubMed  Google Scholar 

  35. Petroff MG, Chen L, Phillips TA, Azzola D, Sedlmayr P, Hunt JS. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol Reprod. 2003;68:1496–1504.

    Article  CAS  PubMed  Google Scholar 

  36. McIntire RH, Morales PJ, Petroff MG, Colonna M, Hunt JS. Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. J Leukoc Biol. 2004;76: 1220–1228.

    Article  CAS  PubMed  Google Scholar 

  37. Pollard JW, Hunt JS, Wiktor-Jedrzejczak W, Stanley ER. A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility. Dev Biol. 1991;148:273–283.

    Article  CAS  PubMed  Google Scholar 

  38. Lidstrom C, Matthiesen L, Berg G, Sharma S, Ernerudh J, Ekerfelt C. Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: implications for suppressor macrophages in decidua. Am J Reprod Immunol. 2003;50:444–452.

    Article  CAS  PubMed  Google Scholar 

  39. Hunt JS, Manning LS, Wood GW. Macrophages in murine uterus are immunosuppressive. Cell Immunol. 1984;85: 499–510.

    Article  CAS  PubMed  Google Scholar 

  40. Keskin DB, Allan DS, Rybalov B, et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16-NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A. 2007;104:3378–3383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Montes MJ, Aleman P, Garcia-Tortosa C, Borja C, Ruiz C, Garcia-Olivares E. Cultured human decidual stromal cells express antigens associated with hematopoietic cells. J Reprod Immunol. 1996;30:53–66.

    Article  CAS  PubMed  Google Scholar 

  42. Olivares EG, Montes MJ, Oliver C, Galindo JA, Ruiz C. Cultured human decidual stromal cells express B7-1 (CD80) and B7-2 (CD86) and stimulate allogeneic T cells. Biol Reprod. 1997;57:609–615.

    Article  CAS  PubMed  Google Scholar 

  43. Oliver C, Cowdrey N, Abadia-Molina AC, Olivares EG. Antigen phenotype of cultured decidual stromal cells of human term decidua. J Reprod Immunol. 1999;45:19–30.

    Article  CAS  PubMed  Google Scholar 

  44. Kitaya K, Yasuda J, Yagi I, Tada Y, Fushiki S, Honjo H. IL-15 expression at human endometrium and decidua. Biol Reprod. 2000;63:683–687.

    Article  CAS  PubMed  Google Scholar 

  45. Hennessy A, Pilmore HL, Simmons LA, Painter DM. A deficiency of placental IL-10 in preeclampsia. J Immunol. 1999;163:3491–3495.

    CAS  PubMed  Google Scholar 

  46. Wilczynski JR, Tchorzewski H, Banasik M, et al. Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2003;109:8–15.

    Article  CAS  PubMed  Google Scholar 

  47. Arnold L, Henry A, Poron F, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007;204:1057–1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cupurdija K, Azzola D, Hainz U, et al. Macrophages of human first trimester decidua express markers associated to alternative activation. Am J Reprod Immunol. 2004;51:117–122.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ramsey H. McIntire PhD.

Additional information

This study was supported by National Institutes of Health grants to JSH (HD24212; HD39878 Project III), and RHM was supported by the University of Kansas Medical Center Biomedical Training Grant.

The authors appreciate the gifts of mouse monoclonal anti-LILRB1 (M401) and anti-LILRB2 (M422) antibodies from Amgen, Inc. The assistance of S. Fernald, University of Kansas School of Medicine Image Analysis Center, with preparation of the figures is greatly appreciated.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McIntire, R.H., Ganacias, K.G. & Hunt, J.S. Programming of Human Monocytes by the Uteroplacental Environment. Reprod. Sci. 15, 437–447 (2008). https://doi.org/10.1177/1933719107314065

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719107314065

Key words

Navigation