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dc.contributor.authorOgando, Jesús-
dc.contributor.authorToribio, María Luisa-
dc.contributor.authorMañes, Santos-
dc.date.accessioned2017-06-23T07:54:45Z-
dc.date.available2017-06-23T07:54:45Z-
dc.date.issued2016-02-03-
dc.identifierdoi: 10.1038/srep20223-
dc.identifierissn: 2045-2322-
dc.identifier.citationScientific Reports 6: 20223 (2016)-
dc.identifier.urihttp://hdl.handle.net/10261/151887-
dc.description.abstractEvidence links aryl hydrocarbon receptor (AHR) activation to rheumatoid arthritis (RA) pathogenesis, although results are inconsistent. AHR agonists inhibit pro-inflammatory cytokine expression in macrophages, pivotal cells in RA aetiopathogenesis, which hints at specific circuits that regulate the AHR pathway in RA macrophages. We compared microRNA (miR) expression in CD14(+) cells from patients with active RA or with osteoarthritis (OA). Seven miR were downregulated and one (miR-223) upregulated in RA compared to OA cells. miR-223 upregulation correlated with reduced Notch3 and Notch effector expression in RA patients. Overexpression of the Notch-induced repressor HEY-1 and co-culture of healthy donor monocytes with Notch ligand-expressing cells showed direct Notch-mediated downregulation of miR-223. Bioinformatics predicted the AHR regulator ARNT (AHR nuclear translocator) as a miR-223 target. Pre-miR-223 overexpression silenced ARNT 3'UTR-driven reporter expression, reduced ARNT (but not AHR) protein levels and prevented AHR/ARNT-mediated inhibition of pro-inflammatory cytokine expression. miR-223 counteracted AHR/ARNT-induced Notch3 upregulation in monocytes. Levels of ARNT and of CYP1B1, an AHR/ARNT signalling effector, were reduced in RA compared to OA synovial tissue, which correlated with miR-223 levels. Our results associate Notch signalling to miR-223 downregulation in RA macrophages, and identify miR-223 as a negative regulator of the AHR/ARNT pathway through ARNT targeting.-
dc.description.sponsorshipSpanish Ministry Economy and Competitiveness (SAF2011-24453 and SAF2014-54475-R to SM; SAF2010-15106 and SAF2013-44857-R to MLT), the Comunidad de Madrid (INMUNOTHERCAN; S2010/BMD-2326 to SM and RAPHYME S2010/BMD-2350 to JLP), the Instituto de Salud Carlos III (ISCIII) (Inflammation and Rheumatic Diseases Network, co-financed by FEDER, RD12/0009; and FIS PI12/00439 to JLP).-
dc.publisherNature Publishing Group-
dc.relation.isversionofPublisher's version-
dc.rightsopenAccess-
dc.titleNotch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients.-
dc.typeartículo-
dc.identifier.doi10.1038/srep20223-
dc.date.updated2017-06-23T07:54:45Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.rights.licensehttps://creativecommons.org/licenses/by/4.0/-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
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