Interleukin 10 Deficiency Exacerbates Toll-Like Receptor 3–Induced Preeclampsia-Like Symptoms in Mice

Abstract

Abstract-Preeclampsia may result from overactivation of the maternal immune system and is characterized by endothelial dysfunction and excessive inflammation. Given the importance of maternal immune system regulation and antiinflammatory cytokines in normotensive pregnancies, we hypothesized that maternal immune system activation via Toll-like receptor 3 during pregnancy would cause preeclampsia-like symptoms in mice, which would be made worse by deficiency of the anti-inflammatory cytokine interleukin 10. The Toll-like receptor 3 agonist polyinosinepolycytidylic acid (poly I:C) caused hypertension, endothelial dysfunction, and proteinuria in mice only when pregnant.In the absence of poly I:C, pregnant interleukin 10 knockout mice exhibited a significant increase in systolic blood pressure, endothelial dysfunction, and serum proinflammatory cytokines, as well as aortic and placental platelet-endothelial cell adhesion molecule expression compared with pregnant wild-type mice. Deficiency of interleukin 10 further augmented these measures in poly I:C-treated pregnant mice. In addition, sera from poly I:C-treated pregnant wild-type mice significantly decreased relaxation responses and increased platelet-endothelial cell adhesion molecule expression in isolated aortas from nonpregnant wild-type mice, and these effects were augmented by sera from poly I:C-treated interleukin 10 knockout mice. Coincubation with recombinant interleukin 10 normalized relaxation responses and platelet-endothelial cell adhesion molecule expression in all of the groups. Collectively, Toll-like receptor 3 activation during pregnancy causes preeclampsia-like symptoms, which are exacerbated by the absence of interleukin 10. Exogenous interleukin 10 treatment had beneficial effects on endothelial function and may be beneficial in women with preeclampsia. Key Words: interleukin 10 Ⅲ endothelium Ⅲ hypertension Ⅲ pregnancy-induced Ⅲ inflammation Ⅲ pregnancy Ⅲ preeclampsia H ypertensive disorders of pregnancy, such as preeclampsia (PE), affect Ϸ10% of all pregnancies, are one of the leading causes of fetal morbidity and mortality, and cause 15% to 20% of maternal deaths worldwide. 1 PE is diagnosed by new-onset hypertension and proteinuria during pregnancy and is associated with endothelial dysfunction, excessive inflammation, and abnormal fetal development. [2][3][4][5] Although the etiology of PE remains unknown, evidence strongly supports a role for the maternal immune system. 6 PE is more common in women with autoimmune diseases and during the first conception, and conversely, the incidence of PE is decreased in women with immune deficiency

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…However, TLR3, TLR7, and TLR8 have all been associated with maternal hypertension in rodent models with preeclampsia-like symptoms (Tinsley et al, 2009;Chatterjee et al, 2011Chatterjee et al, , 2012Chatterjee et al, , 2013Chatterjee et al, , 2015Ishimoto et al, 2013;Kopriva et al, 2013). Moreover TLR7/8, as well as TLR9, from SHR splenocytes evoked the greatest proinflammatory responses to angiotensin II when primed with their respective exogenous ligands (Harwani et al, 2012).…”

Activation of Toll-like receptor 3 increases mouse aortic vascular smooth muscle cell contractility through ERK1/2 pathway

“…On the other hand, George et al [17] found that induction of TLR3 led to [55] demonstrated that activation of TLR3 led to the expression of pro-inflammatory cytokine IL-6 and chemokine MCP-1 in human coronary VSMCs. Group of Mitchell found that maternal hypertension (i.e., preeclampsia) developed in TLR3 agonist-treated animals [45,11,12]. Therefore, a comprehensive understanding of the role of TLR3 in cells of the vasculature including VSMCs is imperative.…”

“…These results lead us to speculate that sustained TLR3 activation can enhance vascular contraction. Chatterjee et al [11] found that TLR3 agonist (Poly I:C) led to endothelial dysfunction, hypertension, and proteinuria in pregnant mice (treatment with Poly I:C, 20 mg/kg, i.p., on days 13, 15, and 17 of pregnancy), but not in nonpregnant mice. Our current study identifies a significant role of TLR3 in male mice.…”

“…Poly I:C is a synthetic analog of dsRNA, a molecular pattern associated with viral infection. This dose and protocol were adopted based on the previous study [11] that found blood pressure elevation using 20 mg/kg every 48 h for 2 weeks. Poly I:C was dissolved in water.…”

Role of Toll-Like Receptor 3 Gene Polymorphisms in Preeclampsia

“…The interaction between the maternal endothelium and activated peripheral blood leukocytes [23] would further reduce, or cross, the threshold for the development of clinical preeclampsia [24]. Several studies have shown that TLR3 activation during pregnancy causes preeclampsia-like symptoms indicating that TLR3 plays a key role in the development of PE [25][26][27].…”