title: Glycodelin-A stimulates interleukin-6 secretion by human monocytes and macrophages through L-selectin and the extracellular signal-regulated kinase pathway.
abstract: Macrophages represent the second major type of decidual leukocytes at the fetomaternal interface. Changes in macrophage number and activity are associated with fetal loss and pregnancy complications. Glycodelin-A (GdA) is an abundant glycoprotein in the first-trimester decidua. It is involved in fetomaternal defense and early placental development through its regulatory activities in various immune cells. The N-glycosylation of GdA mediates the binding and therefore the activities of the molecule. In this study, we studied the biological activities of GdA in the functions of human monocytes/macrophages. GdA was purified from amniotic fluid by affinity chromatography. GdA treatment did not affect the viability, cell death, or phagocytic activity of the monocytes/macrophages. GdA, but not recombinant glycodelin without glycosylation, induced IL-6 production as demonstrated by cytokine array, intracellular staining, and ELISA. GdA also induced phosphorylation of ERK in monocytes/macrophages. The involvement of ERKs in IL-6 induction was confirmed using pharmacological inhibitors. Co-immunoprecipitation showed that L-selectin on the monocytes/macrophages was the binding protein of GdA. Treatment with anti-L-selectin antibody reduced GdA binding and GdA-induced IL-6 production. GdA-treated macrophages suppressed IFN-γ expression by co-cultured T-helper cells in an IL-6-dependent manner. These results show that GdA interacts with L-selectin to induce IL-6 production in monocytes/macrophages by activating the ERK signaling pathway. In turn, the increased IL-6 production suppresses IFN-γ expression in T-helper cells, which may play an important role in inducing a Th-2-polarized cytokine environment that flavors the immunotolerance of the fetoplacental unit.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: Cheuk-Lun
authors.initials: CL
authors.lastname: Lee
authors.forename: Eve Y F
authors.initials: EY
authors.lastname: Lam
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Lam
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
authors.forename: Markku
authors.initials: M
authors.lastname: Seppälä
authors.forename: Ernest H Y
authors.initials: EH
authors.lastname: Ng
authors.forename: William S B
authors.initials: WS
authors.lastname: Yeung
authors.forename: Philip C N
authors.initials: PC
authors.lastname: Chiu
mesh_terms: D000653:Amniotic Fluid / Q000737:chemistry; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000071816:Glycodelin; D006023:Glycoproteins / Q000302:isolation & purification / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000302:isolation & purification / Q000502:physiology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012794:Sialic Acids / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D016207:Cytokines; D000071816:Glycodelin; D006023:Glycoproteins; C508600:IL6 protein, human; D015850:Interleukin-6; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D012794:Sialic Acids; D019041:L-Selectin