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dc.contributor.authorPRESTON, ROGERen
dc.contributor.authorFALLON, PADRAICen
dc.date.accessioned2015-12-11T12:05:26Z
dc.date.available2015-12-11T12:05:26Z
dc.date.issued2014en
dc.date.submitted2014en
dc.identifier.citationGleeson EM, O'Donnell JS, Hams E, Ni Ainle F, Kenny BA, Fallon PG, Preston RJ., Activated Factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine prodution from LPS-stimulated myeloid cells., Haematologica, 99, 1, 2014, 185 - 193en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/75280
dc.descriptionPUBLISHEDen
dc.description.abstractVitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated, receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumor necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumor necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, the findings of this study support a novel function for factor Xa as an endogenous, receptor-associated protein-sensitive, protease-activated receptor 2-dependent regulator of myeloid cell pro-inflammatory cytokine production.en
dc.format.extent185en
dc.format.extent193en
dc.language.isoenen
dc.relation.ispartofseriesHaematologicaen
dc.relation.ispartofseries99en
dc.relation.ispartofseries1en
dc.rightsYen
dc.subjectpathogensen
dc.titleActivated Factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine prodution from LPS-stimulated myeloid cells.en
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/pfallonen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/prestonren
dc.identifier.rssinternalid90082en
dc.identifier.doihttp://dx.doi.org/10.3324/haematol.2013.086918en
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeImmunology, Inflammation & Infectionen
dc.subject.TCDTagBiomedical sciencesen


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