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J Biol Chem 2015 Feb 13;290(7):4422-31

Induction and activation of latent TGF-beta1 is carried out by two distinct domains of Pregnancy-Specific Glycoprotein 1.

Ballesteros A, Mentink-Kane MM, Warren J, Kaplan GG, Dveksler GS


Pregnancy-specific glycoproteins (PSGs) are a family of immunoglobulin (Ig)-like proteins secreted by specialized placental cells. PSG1 structure is comprised of a single Ig-variable like N-terminal domain (N domain) and three Ig-constant-like domains termed A1, A2 and B2. Members of the human and murine PSG family have been shown to induce anti-inflammatory cytokines from monocytes and macrophages, and to stimulate angiogenesis. We recently showed that recombinant forms of PSG1 (PSG1-Fc and PSG1-His) and PSG1 purified from the serum of pregnant women were associated with the immunoregulatory cytokine TGF-beta1 and activated latent TGF-beta1. Here, we sought to examine the requirement of specific PSG1 domains in the activation of latent TGF-beta1. Plasmon surface resonance studies showed that PSG1 directly binds to the small latent complex (SLC) and to the latency-associated peptide (LAP) of TGF-beta1 and that this binding is mediated through the B2-domain. Furthermore, the B2-domain alone was sufficient for activating the SLC. In separate experiments we found that the PSG1- mediated induction of TGF-beta1 secretion in macrophages was dependent on the N-domain. Mutagenesis revealed that 4 amino acids (LYHY) of the CC' loop of the N-domain were required for induction of latent TGF-beta1 secretion. Together our results show that two distinct domains of PSG1 are involved in the regulation of TGF-beta1 and provide a mechanistic framework for how PSGs modulate the immunoregulatory environment at the maternal-fetal interface for successful pregnancy outcome.

Category: Journal Article
PubMed ID: #25548275 DOI: 10.1074/jbc.M114.597518
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2014-12-31 Entry Last Modified: 2015-02-21