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Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia.

Xue P, Zheng M, Gong P, Lin C, Zhou J, Li Y, Shen L, Diao Z, Yan G, Sun H, Hu Y - PLoS ONE (2015)

Bottom Line: Balanced immune responses are essential for the maintenance of successful pregnancy.Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface.This was accompanied with adverse pregnancy outcomes including fetal growth restriction.

View Article: PubMed Central - PubMed

Affiliation: Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.

ABSTRACT
Balanced immune responses are essential for the maintenance of successful pregnancy. Aberrant responses of immune system during pregnancy increase the risk of preeclampsia. Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface. This study aimed to generate a rat model of preeclampsia by lipopolysaccharide (LPS, a TLR4 agonist) administration on gestational day (GD) 5 as rats are subjected to placentation immediately after implantation between GDs 4 and 5, and to assess the contribution of TLR4 signaling to the development of preeclampsia. Single administration of 0.5 μg/kg LPS significantly increased blood pressure of pregnant rats since GD 6 (systolic blood pressure, 124.89 ± 1.79 mmHg versus 119.02 ± 1.80 mmHg, P < 0.05) and urinary protein level since GD 9 (2.02 ± 0.29 mg versus 1.11 ± 0.18 mg, P < 0.01), but barely affected blood pressure or proteinuria of virgin rats compared with those of saline-treated pregnant rats. This was accompanied with adverse pregnancy outcomes including fetal growth restriction. The expression of TLR4 and NF-κB p65 were both increased in the placenta but not the kidney from LPS-treated pregnant rats, with deficient trophoblast invasion and spiral artery remodeling. Furthermore, the levels of inflammatory cytokines were elevated systemically and locally in the placenta from pregnant rats treated with LPS. TLR4 signaling in the placenta was activated, to which that in the placenta of humans with preeclampsia changed similarly. In conclusion, LPS administration to pregnant rats in early pregnancy could elicit TLR4-mediated immune response at the maternal-fetal interface contributing to poor early placentation that may culminate in the preeclampsia-like syndrome.

No MeSH data available.


Related in: MedlinePlus

Cytokine production in different pregnant groups.(A-F), mRNA levels of TNF-α, IL-6 and MCP-1 in the placenta (A-C) and kidney (D-F) from different pregnant groups were measured by qRT-PCR and normalized to that of GAPDH. Data are mean ± SEM, N = 1–2 placentas for 10 rats/group and 1 kidney for 10 rats/group, *P < 0.05 vs. saline-treated pregnant group, N.S. means P > 0.05. (G-H), Concentrations of IL-6 (G) and MCP-1 (H) in the serum from different pregnant groups were measured by ELISA. Data are expressed by mean ± SEM, N = 10 rats per group. *P < 0.05 vs. saline-treated pregnant group.
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pone.0124001.g006: Cytokine production in different pregnant groups.(A-F), mRNA levels of TNF-α, IL-6 and MCP-1 in the placenta (A-C) and kidney (D-F) from different pregnant groups were measured by qRT-PCR and normalized to that of GAPDH. Data are mean ± SEM, N = 1–2 placentas for 10 rats/group and 1 kidney for 10 rats/group, *P < 0.05 vs. saline-treated pregnant group, N.S. means P > 0.05. (G-H), Concentrations of IL-6 (G) and MCP-1 (H) in the serum from different pregnant groups were measured by ELISA. Data are expressed by mean ± SEM, N = 10 rats per group. *P < 0.05 vs. saline-treated pregnant group.

Mentions: Cytokine production in the placenta and kidney from pregnant groups were investigated by qRT-PCR on GD 18. The level of TNF-α mRNA in the placenta and kidney did not show significant differences between pregnant groups (Fig 6A and 6D). However, much stronger signals for both IL-6 and MCP-1 were observed in the placenta (P < 0.05) but not the kidney from the LPS-treated pregnant group than those from the pregnant control group (Fig 6B, 6C, 6E and 6F). ELISA further showed that serum IL-6 and MCP-1 in the LPS-treated pregnant group significantly exceeded those in the pregnant control group (P < 0.05) (Fig 6G and 6H).


Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia.

Xue P, Zheng M, Gong P, Lin C, Zhou J, Li Y, Shen L, Diao Z, Yan G, Sun H, Hu Y - PLoS ONE (2015)

Cytokine production in different pregnant groups.(A-F), mRNA levels of TNF-α, IL-6 and MCP-1 in the placenta (A-C) and kidney (D-F) from different pregnant groups were measured by qRT-PCR and normalized to that of GAPDH. Data are mean ± SEM, N = 1–2 placentas for 10 rats/group and 1 kidney for 10 rats/group, *P < 0.05 vs. saline-treated pregnant group, N.S. means P > 0.05. (G-H), Concentrations of IL-6 (G) and MCP-1 (H) in the serum from different pregnant groups were measured by ELISA. Data are expressed by mean ± SEM, N = 10 rats per group. *P < 0.05 vs. saline-treated pregnant group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4390151&req=5

pone.0124001.g006: Cytokine production in different pregnant groups.(A-F), mRNA levels of TNF-α, IL-6 and MCP-1 in the placenta (A-C) and kidney (D-F) from different pregnant groups were measured by qRT-PCR and normalized to that of GAPDH. Data are mean ± SEM, N = 1–2 placentas for 10 rats/group and 1 kidney for 10 rats/group, *P < 0.05 vs. saline-treated pregnant group, N.S. means P > 0.05. (G-H), Concentrations of IL-6 (G) and MCP-1 (H) in the serum from different pregnant groups were measured by ELISA. Data are expressed by mean ± SEM, N = 10 rats per group. *P < 0.05 vs. saline-treated pregnant group.
Mentions: Cytokine production in the placenta and kidney from pregnant groups were investigated by qRT-PCR on GD 18. The level of TNF-α mRNA in the placenta and kidney did not show significant differences between pregnant groups (Fig 6A and 6D). However, much stronger signals for both IL-6 and MCP-1 were observed in the placenta (P < 0.05) but not the kidney from the LPS-treated pregnant group than those from the pregnant control group (Fig 6B, 6C, 6E and 6F). ELISA further showed that serum IL-6 and MCP-1 in the LPS-treated pregnant group significantly exceeded those in the pregnant control group (P < 0.05) (Fig 6G and 6H).

Bottom Line: Balanced immune responses are essential for the maintenance of successful pregnancy.Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface.This was accompanied with adverse pregnancy outcomes including fetal growth restriction.

View Article: PubMed Central - PubMed

Affiliation: Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.

ABSTRACT
Balanced immune responses are essential for the maintenance of successful pregnancy. Aberrant responses of immune system during pregnancy increase the risk of preeclampsia. Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface. This study aimed to generate a rat model of preeclampsia by lipopolysaccharide (LPS, a TLR4 agonist) administration on gestational day (GD) 5 as rats are subjected to placentation immediately after implantation between GDs 4 and 5, and to assess the contribution of TLR4 signaling to the development of preeclampsia. Single administration of 0.5 μg/kg LPS significantly increased blood pressure of pregnant rats since GD 6 (systolic blood pressure, 124.89 ± 1.79 mmHg versus 119.02 ± 1.80 mmHg, P < 0.05) and urinary protein level since GD 9 (2.02 ± 0.29 mg versus 1.11 ± 0.18 mg, P < 0.01), but barely affected blood pressure or proteinuria of virgin rats compared with those of saline-treated pregnant rats. This was accompanied with adverse pregnancy outcomes including fetal growth restriction. The expression of TLR4 and NF-κB p65 were both increased in the placenta but not the kidney from LPS-treated pregnant rats, with deficient trophoblast invasion and spiral artery remodeling. Furthermore, the levels of inflammatory cytokines were elevated systemically and locally in the placenta from pregnant rats treated with LPS. TLR4 signaling in the placenta was activated, to which that in the placenta of humans with preeclampsia changed similarly. In conclusion, LPS administration to pregnant rats in early pregnancy could elicit TLR4-mediated immune response at the maternal-fetal interface contributing to poor early placentation that may culminate in the preeclampsia-like syndrome.

No MeSH data available.


Related in: MedlinePlus