TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway

• Published in: PloS one 2013-07, Vol.8 (7), p.e67760-e67760
• Main Authors: Kopriva, Shelley E, Chiasson, Valorie L, Mitchell, Brett M, Chatterjee, Piyali
• Format: Article
• Language: English
• Subjects: Achievement tests; Activation; Adult; Algorithms; Animals; Biology; Cytokines; Dehydrogenases; Development and progression; Etiology; Female; Gene expression; Gene Expression Regulation; Genetic aspects; Humans; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immune system; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin; Interleukin 4; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - genetics; Interleukin-4 - metabolism; Internal medicine; Mathematics; Medicine; Mice; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - agonists; MicroRNAs - genetics; MicroRNAs - metabolism; Nephrology; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - metabolism; Pathogens; Physiological aspects; Placenta; Poly (I:C); Poly I-C - pharmacology; Polyinosinic:polycytidylic acid; Pre-Eclampsia - genetics; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Preeclampsia; Pregnancy; Proteinuria; Rodents; Signal Transduction; Stat6 protein; STAT6 Transcription Factor - antagonists & inhibitors; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Studies; Target recognition; TLR3 protein; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 3 - deficiency; Toll-Like Receptor 3 - genetics; Toll-like receptors; Trophoblasts - cytology; Trophoblasts - drug effects; Trophoblasts - metabolism; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067760

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.