Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE2, and TGF-β1

Abstract

Pregnancy-specific glycoproteins (PSGs) are a family of secreted proteins produced by the placenta, which are believed to have a critical role in pregnancy success. Treatment of monocytes with three members of the human PSGs induces interleukin (IL)-10, IL-6, and transforming growth factor-beta(1) (TGF-beta(1)) secretion. To determine whether human and murine PSGs have similar functions and use the same receptor, we treated wild-type and CD9-deficient macrophages with murine PSG17N and human PSG1 and -11. Our data show that murine PSG17N induced secretion of IL-10, IL-6, prostaglandin E(2), and TGF-beta(1) and that CD9 expression is required for the observed induction of cytokines. Therefore, the ability of PSG17 to induce anti-inflammatory cytokines parallels that of members of the human PSG family, albeit human and murine PSGs use different receptors, as CD9-deficient and wild-type macrophages responded equally to human PSGs. We then proceeded to examine the signaling mechanisms responsible for the CD9-mediated response to PSG17. Inhibition of cyclooxygenase 2 significantly reduced the PSG17N-mediated increase in IL-10 and IL-6. Further characterization of the response to PSG17 indicated that cyclic adenosine monophosphate-dependent protein kinase A (PKA) is involved in the up-regulation of IL-10 and IL-6, and it is not required for the induction of TGF-beta(1). Conversely, treatment of macrophages with a PKC inhibitor reduced the PSG17-mediated induction of TGF-beta(1), IL-6, and IL-10 significantly. The induction of anti-inflammatory cytokines by various PSGs supports the hypothesis that these glycoproteins have an essential role in the regulation of the maternal immune response in species with hemochorial placentation.

Expression of the Metastasis Suppressor KAI1 in Decidual Cells at the Human Maternal-Fetal Interface

“…Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages stimulates secretion of various interleukins, prostaglandin E 2 , and TGF␤. 56 Binding of a monoclonal anti-CD82 antibody to KAI1/CD82 on T lymphocytes, apparently acting as a pseudo-ligand, has been shown to induce downstream effects on activation and cytoskeletal reorganization. 57 Most recently, KAI1 expressed on tumor cells was shown to interact with DARC, a cell-surface protein on vascular endothelial cells.…”

CD9 regulates transcription factor GCM1 and ERVWE1 expression through the cAMP/protein kinase A signaling pathway

“…CD9, a member of the tetraspanin superfamily, is required for cell-cell fusions in which fertilization takes place (Le Naour et al 2000) and also in myogenesis (Tachibana & Hemler 1999). In macrophages, CD9 regulates secretions of IL10 and IL6 via the cAMP/PKA signaling pathway (Ha et al 2005). We hypothesized that CD9 regulates ERVWE1 gene expression through cAMP/PKA signaling pathway and a transcription factor GCM1 in human trophoblast cells.…”

Psg18 Is Specifically Expressed in Follicle-associated Epithelium

“…CD9 is the only receptor reported to bind the Psg family proteins including Psg17 and Psg19 (Waterhouse et al, 2002). Given that the highly conserved amino acid sequence and the domain structure among Psgs17, 18 and 19, we speculated that Psg18 might also bind to CD9 (Ha et al, 2005). We found that CD9 is highly expressed by CD11b + DCs that is a major population of DCs residing in the SED in PP (Fig.…”

“…In addition, CD11b + DC was found to highly express the Psg receptor, CD9. The binding of Psgs to CD9 has been reported to induce Th2 cytokines IL-10 and IL-6 as well as TGF-β 1 in human monocytes and murine macrophages (Ha et al, 2005). These observations raise the possibility that Psg18 may condition DCs to produce Th2 cytokines via CD9, although further investigation is required to test this hypothesis.…”