Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.

Hdl Handle:
http://hdl.handle.net/10147/306890
Title:
Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.
Authors:
Gleeson, Eimear M; O'Donnell, James S; Hams, Emily; Ni Ainle, Fionnuala; Kenny, Bridget-Ann; Fallon, Padraic G; Preston, Roger J S
Affiliation:
Ireland.
Citation:
Gleeson EM et al. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells. 2013: Haematologica
Journal:
Haematologica
Issue Date:
19-Jul-2013
URI:
http://hdl.handle.net/10147/306890
DOI:
10.3324/haematol.2013.086918
PubMed ID:
23872307
Abstract:
Vitamin 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 tumour 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 tumour 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, this study supports 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.
Item Type:
Article
Language:
en
Keywords:
BLOOD AND IMMUNE DISORDER
ISSN:
1592-8721

Full metadata record

DC FieldValue Language
dc.contributor.authorGleeson, Eimear Men_GB
dc.contributor.authorO'Donnell, James Sen_GB
dc.contributor.authorHams, Emilyen_GB
dc.contributor.authorNi Ainle, Fionnualaen_GB
dc.contributor.authorKenny, Bridget-Annen_GB
dc.contributor.authorFallon, Padraic Gen_GB
dc.contributor.authorPreston, Roger J Sen_GB
dc.date.accessioned2013-12-16T15:33:23Z-
dc.date.available2013-12-16T15:33:23Z-
dc.date.issued2013-07-19-
dc.identifier.citationGleeson EM et al. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells. 2013: Haematologicaen_GB
dc.identifier.issn1592-8721-
dc.identifier.pmid23872307-
dc.identifier.doi10.3324/haematol.2013.086918-
dc.identifier.urihttp://hdl.handle.net/10147/306890-
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 tumour 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 tumour 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, this study supports 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_GB
dc.languageENG-
dc.language.isoenen
dc.rightsArchived with thanks to Haematologicaen_GB
dc.subjectBLOOD AND IMMUNE DISORDERen_GB
dc.titleActivated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.en_GB
dc.typeArticleen
dc.contributor.departmentIreland.en_GB
dc.identifier.journalHaematologicaen_GB
dc.description.fundingOtheren
dc.description.provinceLeinsteren
dc.description.peer-reviewpeer-reviewen
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