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Induction and activation of latent transforming growth factor-?1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1).

ABSTRACT: Pregnancy-specific glycoproteins (PSGs) are a family of Ig-like proteins secreted by specialized placental cells. The PSG1 structure is composed of a single Ig variable region-like N-terminal domain and three Ig constant region-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 are associated with the immunoregulatory cytokine TGF-?1 and activated latent TGF-?1. Here, we sought to examine the requirement of specific PSG1 domains in the activation of latent TGF-?1. Plasmon surface resonance studies showed that PSG1 directly bound to the small latent complex and to the latency-associated peptide of TGF-?1 and that this binding was mediated through the B2 domain. Furthermore, the B2 domain alone was sufficient for activating the small latent complex. In separate experiments, we found that the PSG1-mediated induction of TGF-?1 secretion in macrophages was dependent on the N-terminal domain. Mutagenesis analysis revealed that four amino acids (LYHY) of the CC' loop of the N-terminal domain were required for induction of latent TGF-?1 secretion. Together, our results show that two distinct domains of PSG1 are involved in the regulation of TGF-?1 and provide a mechanistic framework for how PSGs modulate the immunoregulatory environment at the maternal-fetal interface for successful pregnancy outcome.

SUBMITTER: Ballesteros A

PROVIDER: S-EPMC4326847 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Induction and activation of latent transforming growth factor-β1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1).

Ballesteros Angela A Mentink-Kane Margaret M MM Warren James J Kaplan Gerardo G GG Dveksler Gabriela S GS

The Journal of biological chemistry 20141229 7

Pregnancy-specific glycoproteins (PSGs) are a family of Ig-like proteins secreted by specialized placental cells. The PSG1 structure is composed of a single Ig variable region-like N-terminal domain and three Ig constant region-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 ...[more]

PMID: 25548275

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Project description:Study questionDo all 10 human pregnancy-specific beta 1-glycoproteins (PSGs) and murine PSG23 activate latent transforming growth factor-β1 (TGF-β1)?Summary answerAll human PSGs and murine PSG23 activated latent TGF-β1.What is known alreadyTwo of the 10 members of the PSG1 family, PSG1 and PSG9, were previously shown to activate the soluble small latent complex of TGF-β1, a cytokine with potent immune suppressive functions.Study design, size, durationRecombinant PSGs were generated and tested for their ability to activate the small latent complex of TGF-β1 in a cell-free ELISA-based assay and in a bioassay. In addition, we tested the ability of PSG1 and PSG4 to activate latent TGF-β bound to the extracellular matrix (ECM) or on the membranes of the Jurkat human T-cell line.Participants/materials, setting, methodsRecombinant PSGs were generated by transient transfection and purified with a His-Trap column followed by gel filtration chromatography. The purified PSGs were compared to vehicle (PBS) used as control for their ability to activate the small latent complex of TGF-β1. The concentration of active TGF-β was measured in an ELISA using the TGF-β receptor II as capture and a bioassay using transformed mink epithelial cells that express luciferase in response to active TGF-β. The specificity of the signal was confirmed using a TGF-β receptor inhibitor. We also measured the binding kinetics of some human PSGs for the latent-associated peptide (LAP) of TGF-β using surface plasmon resonance and determined whether PSG1 and PSG4 could activate the large latent complex of TGF-β1 bound to the ECM and latent TGF-β1 bound to the cell membrane. All experiments were performed in triplicate wells and repeated three times.Main results and the role of chanceAll human PSGs activated the small latent complex of TGF-β1 (P < 0.05 vs. control) and showed similar affinities (KD) for LAP. Despite the lack of sequence conservation with its human counterparts, the ability to activate latent TGF-β1 was shared by a member of the murine PSG family. We found that PSG1 and PSG4 activated the latent TGF-β stored in the ECM (P < 0.01) but did not activate latent TGF-β1 bound to glycoprotein A repetitions predominant (GARP) on the surface of Jurkat T cells.Limitations, reasons for cautionThe affinity of the interaction of LAP and PSGs was calculated using recombinant proteins, which may differ from the native proteins in their post-translational modifications. We also utilized a truncated form of murine PSG23 rather than the full-length protein. For the studies testing the ability of PSGs to activate membrane-bound TGF-β1, we utilized the T-cell line Jurkat and Jurkat cells expressing GARP rather than primary T regulatory cells. All the studies were performed in vitro.Wider implications of the findingsHere, we show that all human PSGs activate TGF-β1 and that this function is conserved in at least one member of the rodent PSG family. In vivo PSGs could potentially increase the availability of active TGF-β1 from the soluble and matrix-bound latent forms of the cytokine contributing to the establishment of a tolerogenic environment during pregnancy.Large-scale dataNone.Study funding/competing interest(s)The research was supported by a grant from the Collaborative Health Initiative Research Program (CHIRP). No conflicts of interests are declared by the authors.

Project description:BACKGROUND:Rodent and primate pregnancy-specific glycoprotein (PSG) gene families have expanded independently from a common ancestor and are expressed virtually exclusively in placental trophoblasts. However, within each species, it is unknown whether multiple paralogs have been selected for diversification of function, or for increased dosage of monofunctional PSG. We analysed the evolution of the mouse PSG sequences, and compared them to rat, human and baboon PSGs to attempt to understand the evolution of this complex gene family. RESULTS:Phylogenetic tree analyses indicate that the primate N domains and the rodent N1 domains exhibit a higher degree of conservation than that observed in a comparison of the mouse N1 and N2 domains, or mouse N1 and N3 domains. Compared to human and baboon PSG N domain exons, mouse and rat PSG N domain exons have undergone less sequence homogenisation. The high non-synonymous substitution rates observed in the CFG face of the mouse N1 domain, within a context of overall conservation, suggests divergence of function of mouse PSGs. The rat PSG family appears to have undergone less expansion than the mouse, exhibits lower divergence rates and increased sequence homogenisation in the CFG face of the N1 domain. In contrast to most primate PSG N domains, rodent PSG N1 domains do not contain an RGD tri-peptide motif, but do contain RGD-like sequences, which are not conserved in rodent N2 and N3 domains. CONCLUSION:Relative conservation of primate N domains and rodent N1 domains suggests that, despite independent gene family expansions and structural diversification, mouse and human PSGs retain conserved functions. Human PSG gene family expansion and homogenisation suggests that evolution occurred in a concerted manner that maintains similar functions of PSGs, whilst increasing gene dosage of the family as a whole. In the mouse, gene family expansion, coupled with local diversification of the CFG face, suggests selection both for increased gene dosage and diversification of function. Partial conservation of RGD and RGD-like tri-peptides in primate and rodent N and N1 domains, respectively, supports a role for these motifs in PSG function.

Project description:The aim of the study was to assess whether general practitioners (GPs) monitor and evaluate the health behavior of their patients in the field of a diet, physical activity, and weight control, and whether they provide appropriate counselling as part of this evaluation. Predictors of those activities among physicians were also determined. The cross-sectional study was conducted in the Piotrkowski district among 200 GPs. The questionnaire covered socio-demographic data and lifestyle characteristics of the physicians, their role as healthy lifestyle providers, and whether they assess lifestyle characteristics of their patients and perform healthy lifestyle counselling. More than 60% of the GPs did not evaluate lifestyle features during their patients' examination. In total, 56% of the GPs provided healthy lifestyle recommendations among patients who have not been diagnosed with chronic lifestyle-related diseases but who do not follow healthy recommendations, and 73% of GPs provided recommendations to patients with chronic diseases related to lifestyle. The study showed that the chance to assess lifestyle characteristics of the patients was significantly higher for the GPs who believed that they were obliged to do so (OR = 6.5; p = 0.002). The chance to recommend a healthy lifestyle among patients who have not been diagnosed with chronic lifestyle-related diseases but who do not follow healthy recommendations was 5.9 times higher among the GPs working in the public sector (p < 0.001) and 16.3 times higher for these who believed that they had sufficient knowledge to provide the advice (p = 0.02). The following predictors of providing a healthy lifestyle counselling among patients with diagnosed chronic lifestyle-related diseases were identified: conviction that a GPs is obligated to provide it (OR = 4.4; p = 0.02), sufficient knowledge (OR = 8.7; p = 0.01), and following health recommendations by themselves (OR = 3.9; p = 0.04). Conclusions: The identified predictors are crucial for the development of appropriate strategies aiming at increasing GPs' involvement in preventive measures and consequently at improving the population's health.

Dataset Information

Induction and activation of latent transforming growth factor-?1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1).

Publications

Induction and activation of latent transforming growth factor-β1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1).

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