Abstract
While infection-induced placental inflammation is a common mechanism of adverse pregnancy outcome, some pathogens can also trigger placental apoptosis, and Toll-like receptors (TLRs) mediate this response. Treatment of human first trimester trophoblast cells with bacterial peptidoglycan (PDG) reduces their constitutive secretion of IL-6 protein and induces apoptosis. This apoptotic response is dependent upon the cell’s expression of TLR1, TLR2 and TLR10, and their lack of TLR6, such that ectopic expression of TLR6 prevents PDG-induced apoptosis and restores IL-6 production. In this current study we have identified three microRNAs (miRs) that regulate TLR2-mediated responses in the human trophoblast. Herein we report that miR-329 plays a pivotal role in mediating PDG-induced trophoblast apoptosis and inhibition of IL-6 mRNA expression by targeting the NF-κB subunit, p65. TLR2 activation by PDG upregulates miR-329 expression and inhibits NF-κB p65 and IL-6 mRNA, and this is reversed by the presence of TLR6. Moreover, inhibition of miR-329 prevents PDG-induced inhibition of NF-κB p65 and IL-6 mRNA expression, and restores cell survival. In addition, we have found miR-23a and let-7c to directly regulate PDG-mediated inhibition of IL-6 mRNA. TLR2 activation by PDG upregulates miR23a and let-7c expression and this is reversed by the presence of TLR6. Furthermore, inhibition of both miR23a and let-7c prevents PDG-inhibition of trophoblast IL-6 mRNA expression. Together, our findings suggest that multiple miRs are involved in the molecular regulation of TLR2-mediated responses in the trophoblast towards gram-positive bacterial components.
Highlights
An intrauterine infection can threaten fetal well-being and pregnancy outcome by gaining access to gestational tissues, such as the placenta, and by triggering an immune response [1]
We have previously demonstrated that human first trimester trophoblast cells expressing TLR1, TLR2 and TLR10, but lacking TLR6 (TLR6-) respond to bacterial PDG by undergoing apoptosis with concomitant reduced constitutive IL-6 protein secretion; and this response is reversed in the same cells if they are transfected to express functional TLR6 (TLR6+) [4,11,15]
We have demonstrated that PDG induces apoptosis in human first trimester trophoblast cells that constitutively express TLR2, and its co-receptors, TLR1 and TLR10, but that lack the co-receptor TLR6 [4,11,15]
Summary
An intrauterine infection can threaten fetal well-being and pregnancy outcome by gaining access to gestational tissues, such as the placenta, and by triggering an immune response [1]. The mechanism by which an infection can lead to adverse pregnancy outcome is thought to involve innate immune responses towards the pathogen, leading to excessive inflammation at the maternal-fetal interface [1], and studies focusing on the pathways involved have implicated pattern recognition receptors (PRR), such as the Toll-like receptors (TLRs), as playing an important role [1,4]. While inflammation is a frequent and common mechanism of TLR function in the trophoblast and adverse pregnancy outcome [1], excessive placental apoptosis has been associated with abnormal pregnancies [8,9]. Administration of grampositive bacterial peptidoglycan (PDG) to pregnant mice, rather than inducing inflammation, triggers placental apoptosis [4] and preterm labor [6], as does the gram-positive bacterium, Group B Streptococcus [10]. TLR2 has been shown to mediate this PDG-induced response in the trophoblast [4,11]
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