The immunomodulatory properties of glycodelin-A on human monocyte and macrophage

Abstract

Macrophages contribute to 20-30% of the overall population of leukocytes at the maternal-fetal interface. They are in close proximity with the trophoblast which take part in remodeling of placental tissue, clearing apoptotic cells and controlling trophoblast functions. Glycodelin isoforms comprise a group of secretory glycoproteins with four well defined glycoforms, each with a distinct glycosylation pattern. Glycodelin-A (GdA) is a uterine isoform with glycosylation-dependent immunomodulatory activities that contributes to feto-maternal defense. It is abundantly synthesized in the decidua during the first trimester of pregnancy. In the present study, we hypothesized that GdA may exert immunoregulatory activities on monocyte/macrophage and promotes their development into unique phenotypes for maintaining pregnancy. Monocytic cell line THP-1 and monocytes extracted from human female peripheral blood were used as study model. Macrophages were obtained from peripheral blood or by in vitro differentiation of the monocytes using granulocyte-macrophage colony-stimulating factor. Our results showed that GdA did not affect the proliferation and viability of monocytes and macrophages. GdA was demonstrated to up-regulate the interleukin (IL)-6 secretions in macrophage and monocyte as determined by ELISA and flow cytometry. Suppression of extracellular signal-regulated kinases (ERK) signaling abolished the stimulatory effect of GdA, indicating that GdA increased IL-6 production in monocytes/macrophages via the ERK activation. Interestingly, it has been reported that IL-6 is essential for the process of implantation, trophoblast invasion and embryo development. The inclusion of GdA also increased the indoleamine 2,3-dioxyenase (IDO) expression of macrophage, which subsequently inhibited the lymphocyte proliferation in a coculture study. IDO is a marker of decidual macrophage with immunosuppressive activity through depriving the access to tryptophan by immune cells. Taken together, the present data propose a novel role of GdA in modulating the cytokine profile and development of monocytes/macrophages in order to facilitate human pregnancy.