Published online before print March 16, 2005

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(Journal of Leukocyte Biology. 2005;77:948-957.)
© 2005 by Society for Leukocyte Biology

Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE₂, and TGF-ß₁

Cam T. Ha^*, Roseann Waterhouse^*, Jennifer Wessells, Julie A. Wu^* and Gabriela S. Dveksler^*,1

^* Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and
Laboratory of Protein Dynamics and Signaling, National Cancer Institute-Frederick, Maryland

¹ Correspondence: Department of Pathology, USUHS, 4301 Jones Bridge Rd., Bethesda, MD 20814. E-mail: gdveksler{at}usuhs.mil

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-ß₁ (TGF-ß₁) 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 E₂, and TGF-ß₁ 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-ß₁. Conversely, treatment of macrophages with a PKC inhibitor reduced the PSG17-mediated induction of TGF-ß₁, 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.

Key Words: reproductive immunology • cytokines

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