title: TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Scott & White Healthcare/Texas A&M Health Science Center, Temple, Texas, USA.
authors.forename: Shelley E
authors.initials: SE
authors.lastname: Kopriva
authors.forename: Valorie L
authors.initials: VL
authors.lastname: Chiasson
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
authors.forename: Piyali
authors.initials: P
authors.lastname: Chatterjee
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000172:deficiency / Q000235:genetics*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D015847:Interleukin-4; D011070:Poly I-C