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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

Expression of TLR4, NF-κB p65 and cytokines in human normal pregnancy and preeclampsia.(A-C), Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded placental tissue sections (4 μm) from human normal pregnancy and preeclampsia. Corresponding concentrations of anti-IgG served as non-specific controls (C). Magnification 400 ×. Bar 100 μm. (D-E), mRNA levels of IL-6 (D) and MCP-1 (E) in the placenta from normal pregnancy and preeclampsia. IL-6 and MCP-1 mRNA levels were measured by qRT-PCR and normalized to that of GAPDH. (F-G) Serum levels of IL-6 (F) and MCP-1(G) in human normal pregnancy and preeclampsia were quantitatively measured by ELISA. Data are expressed by mean ± SEM, N = 10. *Means P < 0.05.
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pone.0124001.g007: Expression of TLR4, NF-κB p65 and cytokines in human normal pregnancy and preeclampsia.(A-C), Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded placental tissue sections (4 μm) from human normal pregnancy and preeclampsia. Corresponding concentrations of anti-IgG served as non-specific controls (C). Magnification 400 ×. Bar 100 μm. (D-E), mRNA levels of IL-6 (D) and MCP-1 (E) in the placenta from normal pregnancy and preeclampsia. IL-6 and MCP-1 mRNA levels were measured by qRT-PCR and normalized to that of GAPDH. (F-G) Serum levels of IL-6 (F) and MCP-1(G) in human normal pregnancy and preeclampsia were quantitatively measured by ELISA. Data are expressed by mean ± SEM, N = 10. *Means P < 0.05.

Mentions: Differences in the expression of TLR4 and its downstream target NF-κB p65 between the control and severe preeclampsia placenta were examined by immunostaining (Fig 7A and 7B). As shown in Fig 7A, TLR4 was predominantly expressed by syncytiotrophoblast in the term placental villi. TLR4 expression in severe preeclampsia placenta significantly increased in comparison to that in the control. Meanwhile, TLR4 positive trophoblasts showed higher levels of NF-κB p65 (Fig 7B).


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)

Expression of TLR4, NF-κB p65 and cytokines in human normal pregnancy and preeclampsia.(A-C), Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded placental tissue sections (4 μm) from human normal pregnancy and preeclampsia. Corresponding concentrations of anti-IgG served as non-specific controls (C). Magnification 400 ×. Bar 100 μm. (D-E), mRNA levels of IL-6 (D) and MCP-1 (E) in the placenta from normal pregnancy and preeclampsia. IL-6 and MCP-1 mRNA levels were measured by qRT-PCR and normalized to that of GAPDH. (F-G) Serum levels of IL-6 (F) and MCP-1(G) in human normal pregnancy and preeclampsia were quantitatively measured by ELISA. Data are expressed by mean ± SEM, N = 10. *Means P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124001.g007: Expression of TLR4, NF-κB p65 and cytokines in human normal pregnancy and preeclampsia.(A-C), Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded placental tissue sections (4 μm) from human normal pregnancy and preeclampsia. Corresponding concentrations of anti-IgG served as non-specific controls (C). Magnification 400 ×. Bar 100 μm. (D-E), mRNA levels of IL-6 (D) and MCP-1 (E) in the placenta from normal pregnancy and preeclampsia. IL-6 and MCP-1 mRNA levels were measured by qRT-PCR and normalized to that of GAPDH. (F-G) Serum levels of IL-6 (F) and MCP-1(G) in human normal pregnancy and preeclampsia were quantitatively measured by ELISA. Data are expressed by mean ± SEM, N = 10. *Means P < 0.05.
Mentions: Differences in the expression of TLR4 and its downstream target NF-κB p65 between the control and severe preeclampsia placenta were examined by immunostaining (Fig 7A and 7B). As shown in Fig 7A, TLR4 was predominantly expressed by syncytiotrophoblast in the term placental villi. TLR4 expression in severe preeclampsia placenta significantly increased in comparison to that in the control. Meanwhile, TLR4 positive trophoblasts showed higher levels of NF-κB p65 (Fig 7B).

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