Published online before print March 16, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0804453

Received for publication August 13, 2004.
Revised February 15, 2005.
Accepted for publication February 17, 2005.

Article

Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE₂, and TGF-₁

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

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

^@ To whom correspondence should be addressed. E-mail: gdveksler{at}usuhs.mil.

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-₁ (TGF-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 E₂, and TGF-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-₁. Conversely, treatment of macrophages with a PKC inhibitor reduced the PSG17-mediated induction of TGF-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.

Key Words: reproductive immunology • cytokines

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