Cytokines and Chemokines during Human Embryo Implantation: Roles in Implantation and Early Placentation

ABSTRACT

The complex processes of embryo implantation and early placentation require a plethora of locally acting molecules, which are themselves tightly regulated. Among these are cytokines (including chemotactic chemokines), which are synthesized by several cell types at the maternal-fetal interface. Those produced by endometrial epithelium may be secreted apically into the uterine lumen, where they affect blastocyst development, migration, and attachment, or basally with effects on the transformation of the underlying stroma. Decidualized stromal cells, which subsequently form a major component of the decidua of pregnancy, also produce cytokines that act to drive the decidualization process and chemokines that are chemoattractants both for leukocytes such as uterine natural killer cells and macrophages, and for trophoblast migration. Activated leukocytes within the developing decidua also contribute regulatory cytokines to the local microenvironment. Disturbances in the production of individual cytokines have been demonstrated in the endometrium of some infertile women and in those with recurrent miscarriage. It is important to establish whether a signature of endometrial cytokines may provide a clinically useful indication of women who will experience difficulty in establishing a viable pregnancy.

Cytokine - chemokine - implantation - placentation - infertility - miscarriage

REFERENCES

• 1 Robertson S A. Cytokines. In: Knobil E, Neill J Encyclopedia of Reproduction. San Diego, CA; Academic Press 1998: 809-822
• 2 Bacon K, Baggiolini M, Broxmeyer H et al.. Chemokine/chemokine receptor nomenclature.  J Interferon Cytokine Res. 2002;  22(10) 1067-1068
• 3 Kunkel E J, Butcher E C. Plasma-cell homing.  Nat Rev Immunol. 2003;  3(10) 822-829
• 4 Proost P, Struyf S, Van Damme J. Natural post-translational modifications of chemokines.  Biochem Soc Trans. 2006;  34(pt 6) 997-1001
• 5 Li Q, Park P W, Wilson C L, Parks W C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury.  Cell. 2002;  111(5) 635-646
• 6 Sherwin J R, Sharkey A M, Cameo P et al.. Identification of novel genes regulated by chorionic gonadotropin in baboon endometrium during the window of implantation.  Endocrinology. 2007;  148(2) 618-626
• 7 Giudice L C. Application of functional genomics to primate endometrium: insights into biological processes.  Reprod Biol Endocrinol. 2006;  4(suppl 1) S4
• 8 Salamonsen L A, Lathbury L J. Endometrial leukocytes and menstruation.  Hum Reprod Update. 2000;  6(1) 16-27
• 9 Dimitriadis E, White C A, Jones R L, Salamonsen L A. Cytokines, chemokines and growth factors in endometrium related to implantation.  Hum Reprod Update. 2005;  11(6) 613-630
• 10 Robertson S A. GM-CSF regulation of embryo development and pregnancy.  Cytokine Growth Factor Rev. 2007;  18 287-298
• 11 Red-Horse K, Drake P M, Fisher S J. Human pregnancy: the role of chemokine networks at the fetal-maternal interface.  Expert Rev Mol Med. 2004;  6 1-14
• 12 Hannan N J, Salamonsen L A. Role of chemokines in the endometrium and in embryo implantation.  Curr Opin Obstet Gynecol. 2007;  19(3) 266-272
• 13 Jones R L, Hannan N J, Kaitu'u T J, Zhang J, Salamonsen L A. Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation.  J Clin Endocrinol Metab. 2004;  89(12) 6155-6167
• 14 Hannan N J, Jones R L, Critchley H O et al.. Coexpression of fractalkine and its receptor in normal human endometrium and in endometrium from users of progestin-only contraception supports a role for fractalkine in leukocyte recruitment and endometrial remodeling.  J Clin Endocrinol Metab. 2004;  89(12) 6119-6129
• 15 Vogiagis D, Marsh M M, Fry R C, Salamonsen L A. Leukaemia inhibitory factor in human endometrium throughout the menstrual cycle.  J Endocrinol. 1996;  148(1) 95-102
• 16 Stewart C L, Kaspar P, Brunet L J et al.. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.  Nature. 1992;  359(6390) 76-79
• 17 Robb L, Li R, Hartley L, Nandurkar H H, Koentgen F, Begley C G. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation.  Nat Med. 1998;  4(3) 303-308
• 18 Laird S M, Tuckerman E M, Dalton C F, Dunphy B C, Li T C, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture.  Hum Reprod. 1997;  12(3) 569-574
• 19 Mikolajczyk M, Skrzypczak J, Szymanowski K, Wirstlein P. The assessment of LIF in uterine flushing-a possible new diagnostic tool in states of impaired fertility.  Reprod Biol. 2003;  3(3) 259-270
• 20 Florio P, Severi F M, Luisi S et al.. Endometrial expression and secretion of activin A, but not follistatin, increase in the secretory phase of the menstrual cycle.  J Soc Gynecol Investig. 2003;  10(4) 237-243
• 21 Ledee-Bataille N. Secreted cytokines in the uterine lumina are predictive of subsequent implantation. Presence of IL18 in the uterine flushing.  J Gynecol Obstet Biol Reprod (Paris). 2004;  33(1 Pt 2) S29-S32
• 22 Dunglison G F, Barlow D H, Sargent I L. Leukaemia inhibitory factor significantly enhances the blastocyst formation rates of human embryos cultured in serum-free medium.  Hum Reprod. 1996;  11(1) 191-196
• 23 Lee K Y, Jeong J W, Wang J et al.. Bmp2 is critical for the murine uterine decidual response.  Mol Cell Biol. 2007;  27 5468-5478
• 24 Tierney E P, Tulac S, Huang S T, Giudice L C. Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation.  Physiol Genomics. 2003;  16(1) 47-66
• 25 Jones R L, Stoikos C, Findlay J K, Salamonsen L A. TGF-beta superfamily expression and actions in the endometrium and placenta.  Reproduction. 2006;  132(2) 217-232
• 26 Lash G E, Otun H A, Innes B A et al.. Interferon-gamma inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels.  FASEB J. 2006;  20(14) 2512-2518
• 27 Hanna J, Goldman-Wohl D, Hamani Y et al.. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.  Nat Med. 2006;  12(9) 1065-1074
• 28 Hannan N J, Jones R L, White C A, Salamonsen L A. The chemokines, CX3CL1, CCL14, and CCL4, promote human trophoblast migration at the feto-maternal interface.  Biol Reprod. 2006;  74(5) 896-904
• 29 Popovici R M, Betzler N K, Krause M S et al.. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model.  Endocrinology. 2006;  147(12) 5662-5675
• 30 Hess A P, Hamilton A E, Talbi S et al.. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators.  Biol Reprod. 2007;  76(1) 102-117
• 31 Bulmer J N, Longfellow M, Ritson A. Leukocytes and resident blood cells in endometrium.  Ann N Y Acad Sci. 1991;  622 57-68
• 32 Salamonsen L A, Zhang J, Brasted M. Leukocyte networks and human endometrial remodelling.  J Reprod Immunol. 2002;  57(1-2) 95-108
• 33 Moffett-King A. Natural killer cells and pregnancy.  Nat Rev Immunol. 2002;  2(9) 656-663
• 34 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(1) 75-80
• 35 Verma S, Hiby S E, Loke Y W, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15.  Biol Reprod. 2000;  62(4) 959-968
• 36 Meter R A, Wira C R, Fahey J V. Secretion of monocyte chemotactic protein-1 by human uterine epithelium directs monocyte migration in culture.  Fertil Steril. 2005;  84(1) 191-201
• 37 Lockwood C J, 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(2) 445-452
• 38 van den Heuvel M J, Xie X, Tayade C et al.. A review of trafficking and activation of uterine natural killer cells.  Am J Reprod Immunol. 2005;  54(6) 322-331
• 39 Wu X, Jin L P, Yuan M M, Zhu Y, Wang M Y, Li D J. Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1.  J Immunol. 2005;  175(1) 61-68
• 40 Genbacev O D, Prakobphol A, Foulk R A et al.. Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface.  Science. 2003;  299(5605) 405-408
• 41 Dominguez F, Yanez-Mo M, Sanchez-Madrid F, Simon C. Embryonic implantation and leukocyte transendothelial migration: different processes with similar players?.  FASEB J. 2005;  19(9) 1056-1060
• 42 Aplin J D. Embryo implantation: the molecular mechanism remains elusive.  Reprod Biomed Online. 2006;  13(6) 833-839
• 43 Chapman G A, Moores K E, Gohil J et al.. The role of fractalkine in the recruitment of monocytes to the endothelium.  Eur J Pharmacol. 2000;  392(3) 189-195
• 44 Sato Y, Higuchi T, Yoshioka S, Tatsumi K, Fujiwara H, Fujii S. Trophoblasts acquire a chemokine receptor, CCR1, as they differentiate towards invasive phenotype.  Development. 2003;  130(22) 5519-5532
• 45 Red-Horse K, Drake P M, Gunn M D, Fisher S J. Chemokine ligand and receptor expression in the pregnant uterus: reciprocal patterns in complementary cell subsets suggest functional roles.  Am J Pathol. 2001;  159(6) 2199-2213
• 46 Red-Horse K, Kapidzic M, Zhou Y, Feng K T, Singh H, Fisher S J. EPHB4 regulates chemokine-evoked trophoblast responses: a mechanism for incorporating the human placenta into the maternal circulation.  Development. 2005;  132(18) 4097-4106
• 47 Norwitz E R, Schust D J, Fisher S J. Implantation and the survival of early pregnancy.  N Engl J Med. 2001;  345(19) 1400-1408
• 48 Wang H, Dey S K. Roadmap to embryo implantation: clues from mouse models.  Nat Rev Genet. 2006;  7(3) 185-199
• 49 Barker D J, Clark P M. Fetal undernutrition and disease in later life.  Rev Reprod. 1997;  2(2) 105-112
• 50 Maher E R, Afnan M, Barratt C L. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs?.  Hum Reprod. 2003;  18(12) 2508-2511
• 51 Thompson J G, Kind K L, Roberts C T, Robertson S A, Robinson J S. Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution?.  Hum Reprod. 2002;  17(11) 2783-2786
• 52 Ledee-Bataille N, Lapree-Delage G, Taupin J L, Dubanchet S, Frydman R, Chaouat G. Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation.  Hum Reprod. 2002;  17(1) 213-218
• 53 Makkar G, Ng E H, Yeung W S, Ho P C. Reduced expression of interleukin-11 and interleukin-6 in the periimplantation endometrium of excessive ovarian responders during in vitro fertilization treatment.  J Clin Endocrinol Metab. 2006;  91(8) 3181-3188
• 54 Dimitriadis E, Stoikos C, Stafford-Bell M et al.. Interleukin-11, IL-11 receptor alpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window.  J Reprod Immunol. 2006;  69(1) 53-64
• 55 Jasper M J, Tremellen K P, Robertson S A. Reduced expression of IL-6 and IL-1 alpha mRNAs in secretory phase endometrium of women with recurrent miscarriage.  J Reprod Immunol. 2007;  73(1) 74-84
• 56 Giudice L C, Telles T L, Lobo S, Kao L. The molecular basis for implantation failure in endometriosis: on the road to discovery.  Ann N Y Acad Sci. 2002;  955 252-264
• 57 Damario M A, Lesnick T G, Lessey B A et al.. Endometrial markers of uterine receptivity utilizing the donor oocyte model.  Hum Reprod. 2001;  16(9) 1893-1899
• 58 Laird S M, Tuckerman E M, Cork B A, Linjawi S, Blakemore A I, Li T C. A review of immune cells and molecules in women with recurrent miscarriage.  Hum Reprod Update. 2003;  9(2) 163-174
• 59 Emmer P M, Nelen W L, Steegers E A, Hendriks J C, Veerhoek M, Joosten I. Peripheral natural killer cytotoxicity and CD56(pos)CD16(pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion.  Hum Reprod. 2000;  15(5) 1163-1169
• 60 Quack K C, Vassiliadou N, Pudney J, Anderson D J, Hill J A. Leukocyte activation in the decidua of chromosomally normal and abnormal fetuses from women with recurrent abortion.  Hum Reprod. 2001;  16(5) 949-955
• 61 Laird S M, Tuckerman E M, Li T C. Cytokine expression in the endometrium of women with implantation failure and recurrent miscarriage.  Reprod Biomed Online. 2006;  13(1) 13-23
• 62 Whitcomb B W, Schisterman E F, Klebanoff M A et al.. Circulating chemokine levels and miscarriage.  Am J Epidemiol. 2007;  166 323-331