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Inhibition of trophoblast cell invasion by TGFB1, 2, and 3 is associated with a decrease in active proteases
Gendie E Lash1, Harry A Otun, Barbara A Innes
1Schools of Surgical and Reproductive Sciences, University of Newcastle upon Tyne, Newcastle Tyne NE2 4HH, United Kingdom. g.e.lash@ncl.ac.uk
Abstract:
Invasion of extravillous trophoblast cells into the uterus in human pregnancy is tightly regulated. The transforming growth factor-beta (TGFB) family has been suggested to play a role in controlling this process. We hypothesized that TGFB1, 2, and 3 would inhibit the invasive capacity of extravillous trophoblast cells. We also studied trophoblast apoptosis and proliferation and secreted protease levels as potential mechanisms by which these cytokines may act. Inhibition of endogenous TGFB1, 2, and 3 with neutralizing antibodies increased the invasive capacity of extravillous trophoblast cells derived from placental explants. Similarly, addition of exogenous TGFB1, 2, and 3 inhibited the invasive capacity of these cells in a dose-dependent manner. Proliferation of trophoblast in the placental explants did not alter in response to any of the cytokines tested. Apoptosis of villous and extravillous trophoblast did not alter in response to TGFB1, 2, and 3. There was a reduction in secreted levels of matrix metalloproteinase (MMP) 9 and urokinase plasminogen activator in response to all three cytokines. MMP2 and tissue inhibitor of metalloproteinase 1 and 3 levels were not altered. These results suggest that TGFB1, 2, and 3 inhibit trophoblast invasion by a mechanism dependent on reduced protease activity.
Insights
Transforming growth factor-beta (TGFB) 1, 2, and 3 inhibit human trophoblast invasion by reducing protease activity. This finding is crucial for understanding early pregnancy regulation and potential therapeutic targets.
Area of Science:
- Reproductive Biology
- Cell Biology
- Molecular Endocrinology
Background:
- Human pregnancy involves tightly regulated extravillous trophoblast invasion into the uterus.
- The transforming growth factor-beta (TGFB) family is implicated in controlling trophoblast invasion.
- Specific roles of TGFB1, TGFB2, and TGFB3 in this process require elucidation.
Purpose of the Study:
- To investigate the hypothesis that TGFB1, TGFB2, and TGFB3 inhibit extravillous trophoblast cell invasion.
- To explore potential mechanisms including trophoblast apoptosis, proliferation, and protease secretion.
- To determine the dose-dependent effects of TGFB1, TGFB2, and TGFB3 on trophoblast invasion.
Main Methods:
- Utilized placental explants to assess extravillous trophoblast invasion.
- Employed neutralizing antibodies to inhibit endogenous TGFB1, TGFB2, and TGFB3.
- Administered exogenous TGFB1, TGFB2, and TGFB3 to evaluate dose-dependent effects.
- Quantified trophoblast proliferation, apoptosis, and secreted protease levels (MMP-9, uPA).
Main Results:
- Inhibition of endogenous TGFB1-3 increased trophoblast invasion.
- Exogenous TGFB1-3 dose-dependently inhibited trophoblast invasion.
- TGFB1-3 did not significantly alter trophoblast proliferation or apoptosis.
- TGFB1-3 reduced secreted levels of matrix metalloproteinase (MMP)-9 and urokinase plasminogen activator (uPA).
Conclusions:
- TGFB1, TGFB2, and TGFB3 inhibit extravillous trophoblast invasion.
- The inhibitory mechanism is linked to reduced activity of secreted proteases, specifically MMP-9 and uPA.
- These findings highlight the role of TGFB signaling in regulating key aspects of early human pregnancy.
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