Do double-stranded RNA receptors play a role in preeclampsia?

Chatterjee, Piyali; Weaver, Laura; Chiasson, Valorie L; Young, Kristina J.; Mitchell, Brett M.

doi:10.1016/j.placenta.2010.12.026

Cited by 22 publications

(25 citation statements)

References 60 publications

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“…Out of the many TLRs, double-stranded RNA viruses bind to TLR3 leading to activation of the adaptor molecule TRIF, which is involved in IRF3 and NF-κB activation, and subsequently leads to IFN-β production and the expression of IFN-inducible genes [10]. Several studies link viral infections with a 2-fold increased risk of developing PE [11], [12]. We have reported previously that TLR3 activation is increased in placentas of women with PE and that activating the maternal immune system with the TLR3 agonist poly I:C in pregnant mice leads to PE-like symptoms [13], [14].…”

Section: Introductionmentioning

confidence: 99%

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

et al. 2013

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Several clinical studies have reported increased placental miR-210 expression in women with PE compared to normotensive women, but whether miR-210 plays a role in the etiology of PE is unknown. We reported that activation of TLR3 produces the PE-like symptoms of hypertension, endothelial dysfunction, and proteinuria in mice only when pregnant, but whether TLR3 activation in pregnant mice and human cytotrophoblasts (CTBs) increases miR-210 and modulates its targets related to inflammation are unknown. Placental miR-210 levels were increased significantly in pregnant mice treated with the TLR3 agonist poly I:C (P-PIC). Both HIF-1α and NF-κBp50, known to bind the miR-210 promoter and induce its expression, were also increased significantly in placentas of P-PIC mice. Target identification algorithms and gene ontology predicted STAT6 as an inflammation-related target of miR-210 and STAT6 was decreased significantly in placentas of P-PIC mice. IL-4, which is regulated by STAT6 and increases during normotensive pregnancy, failed to increase in serum of P-PIC mice. P-PIC TLR3 KO mice did not develop hypertension and placental HIF-1α, NF-κBp50, miR-210, STAT6, and IL-4 levels were unchanged. To determine the placental etiology, treatment of human CTBs with poly I:C significantly increased HIF-1α, NF-κBp50, and miR-210 levels and decreased STAT6 and IL-4 levels. Overexpression of miR-210 in CTBs decreased STAT6 and IL-4 while inhibition of miR-210 increased STAT6 and IL-4. These findings demonstrate that TLR3 activation induces placental miR-210 via HIF-1α and NF-κBp50 leading to decreased STAT6 and IL-4 levels and this may contribute to the development of PE.

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Section: Introductionmentioning

confidence: 99%

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

et al. 2013

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“…[50], [51] demonstrated that all the three dsRNAs receptors, TLR-3, RIG-I and IFIH1, are activated in placentas of mice and women with preeclampsia (PE), a pregnancy-specific syndrome characterized by excessive maternal immune system activation, inflammation, and endothelial dysfunction, causing hypertension. Chatterjee et al .…”

Section: Discussionmentioning

confidence: 99%

“…Our results suggesting that IFIH1 gene expression is increased in mononuclear cell from T1DM patients with AH is in agreement with the data of Chatterjee et al . [50], [51] indicating that high expression of dsRNA receptors may have a role in hypertension. Therefore, it seems reasonable to suggest that T1DM patients carrying the A/A genotype may have a lower risk for developing AH due to a decreased IFIH1 gene expression and, consequently, a lesser inflammatory environment.…”

Section: Discussionmentioning

confidence: 99%

The A Allele of the rs1990760 Polymorphism in the IFIH1 Gene Is Associated with Protection for Arterial Hypertension in Type 1 Diabetic Patients and with Expression of This Gene in Human Mononuclear Cells

et al. 2013

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BackgroundThe rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM.MethodsFrequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR.ResultsOur data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1×10−10) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7–2.0) vs. 1.8 (1.3–7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus.ConclusionsOur results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH.

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“…There is also interest in the potential role of viral PAMPs or related DAMPs from necrotic cells in preeclampsia. Activation via TLR3 or the RLRs RIG-1 and MDA-5 leading to downstream inflammation, anti-angiogenesis and oxidative stress converging on endothelial dysfunction has been postulated (Chatterjee, Weaver et al 2011). …”

Section: Prrs and Adverse Pregnancy Outcomesmentioning

confidence: 99%