The biological activities of glycodelin-A on human monocytes and macrophages

Abstract

The fetal-maternal interface is an immunologically privileged site where the semi-allogeneic fetus is protected from the maternal immune system. Macrophage represents the second major type (20-30%) of the decidual leukocyte. It functions as important regulator of pregnancy processes such as fetal tolerance, placental development and onset of labor. Changes in macrophage number and activity have been associated with fetal loss and pregnancy complications, including intrauterine growth restriction and preeclampsia. Glycodelin-A (Gd-A) is an abundant glycoprotein with ubiquitous distribution in the first trimester deciduas. It is suggested to be involved in early placental development by its regulatory activities on various immune cells. In this study, it is hypothesized that Gd-A has regulatory role in monocyte/macrophage functions and differentiation.

The first objective examined the role of Gd-A in the biological activities of monocytes and macrophages. Gd-A was found to bind to the monocytic cell lines THP-1 and U937, blood monocytes, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated macrophages, phorbol 12-myristate 13-acetate-differentiated macrophage and blood macrophages. Gd-A did not affect the viability, proliferation, cell death and phagocytic activity of monocytes and macrophages.

The second objective examined the effect of Gd-A on the cytokine secretion of monocytes and macrophages. Gd-A treatment increased the IL-6 production in monocytes and macrophages. IL-6 was associated with the development and growth of the fetal-placental unit. Gd-A also induced the extracellular signal regulated kinases (ERK) activation. The involvement of ERK in stimulating IL-6 production was confirmed by using pharmacological inhibitors.

Monocytes in the blood stream are attracted and residue into the deciduas, which differentiated into macrophage under the influence of various decidual soluble factors. Therefore, the third objective studied the possible involvement of Gd-A on the differentiation of monocytes into macrophages. Co-treatment of Gd-A during the GM-CSF-induced differentiation of monocytes stimulated the indoleamine 2,3-dioxygenase (IDO-1) expression and activity in differentiated macrophages. These differentiated macrophages inhibited the proliferation of autologous peripheral blood mononuclear cell in the co-culture system by G0/G1 cell cycle arrest. IDO-1 is one of the reported decidual macrophage markers. It has been suggested to be involved in establishing the tolerogenic environment during pregnancy through L-tryptophan depletion. The increase in IDO-1 expression may be regulated by PKC signaling pathway.

Taken together, this thesis reported a novel role of Gd-A on the monocyte differentiation. The present results enhance our knowledge on the regulation of early placentation in human and may shed light on understanding the pathology of complicated pregnancy due to macrophage dysfunction.