Gonadotropin-releasing hormone-regulated chemokine expression in human placentation.
Placental expression of gonadotropin-releasing hormone (GnRH)-I and II, as well as their cognate receptor, coincides with a period of extensive remodeling of the maternal-fetal interface, near the end of the first trimester of pregnancy. To further define the role of GnRH in human placentation, we performed a microarray screen of HTR-8/SVneo trophoblasts to identify GnRH-regulated genes and their roles in placentation. This screen revealed that GnRH regulates the expression of four angiogenic chemokines: CXCL2, CXCL3, CXCL6, and CXCL8. The microarray data were subsequently confirmed by an extensive Q-PCR time-course analysis. CXCL8, a representative chemokine, was selected for further analysis and shown to be strongly expressed by trophoblasts at the maternal-fetal interface of the human placenta, as well as to accumulate in a GnRH-dependent manner in trophoblast-conditioned media in culture. Trophoblasts were subsequently shown to recruit lymphocytes (Jurkat T cells and primary peripheral blood T and uterine natural killer cells) in chemotaxis assays and this was shown to be GnRH dependent. Furthermore, this recruitment was shown to occur via the release of CXCR1/CXCR2 interacting chemokines, such as the CXCLs investigated in this study. This novel regulation of chemokines by GnRH signaling demonstrates the role of GnRH in regulating the recruitment of lymphocytes to the decidua and the possibility of a direct effect on spiral artery remodeling via the release of proangiogenic chemokines and secondary effects via release of angiogenic factors by recruited lymphocytes.
Cavanagh
P Craig
PC
Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada.
Dunk
Caroline
C
Pampillo
Macarena
M
Szereszewski
Jacob M
JM
Taylor
Jay E
JE
Kahiri
Caroline
C
Han
Victor
V
Lye
Stephen
S
Bhattacharya
Moshmi
M
Babwah
Andy V
AV
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D002064:Buserelin / Q000494:pharmacology; D002461:Cell Line, Transformed; D054426:Chemokine CXCL2 / Q000378:metabolism; D054427:Chemokine CXCL6 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling / Q000379:methods; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014327:Trophoblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D042501:Angiogenic Proteins; C499706:CXCL2 protein, human; C499707:CXCL3 protein, human; C515503:CXCL6 protein, human; C508606:CXCL8 protein, human; D054426:Chemokine CXCL2; D054427:Chemokine CXCL6; D018925:Chemokines; D019743:Chemokines, CXC; D017077:Culture Media, Conditioned; D006727:Hormone Antagonists; D016209:Interleukin-8; D009842:Oligopeptides; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C057022:iturelix; D002064:Buserelin