Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.
Authors
Gleeson, Eimear MO'Donnell, James S
Hams, Emily
Ni Ainle, Fionnuala
Kenny, Bridget-Ann
Fallon, Padraic G
Preston, Roger J S
Affiliation
Ireland.Issue Date
2013-07-19Keywords
BLOOD AND IMMUNE DISORDER
Metadata
Show full item recordCitation
Gleeson EM et al. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells. 2013: HaematologicaJournal
HaematologicaDOI
10.3324/haematol.2013.086918PubMed ID
23872307Abstract
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
ArticleLanguage
enISSN
1592-8721ae974a485f413a2113503eed53cd6c53
10.3324/haematol.2013.086918
Scopus Count
Collections
Related articles
- Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.
- Authors: Hara T, Phuong PT, Fukuda D, Yamaguchi K, Murata C, Nishimoto S, Yagi S, Kusunose K, Yamada H, Soeki T, Wakatsuki T, Imoto I, Shimabukuro M, Sata M
- Issue date: 2018 Oct 16
- Melatonin modulates TLR4-mediated inflammatory genes through MyD88- and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells.
- Authors: Xia MZ, Liang YL, Wang H, Chen X, Huang YY, Zhang ZH, Chen YH, Zhang C, Zhao M, Xu DX, Song LH
- Issue date: 2012 Nov
- Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy.
- Authors: Oe Y, Hayashi S, Fushima T, Sato E, Kisu K, Sato H, Ito S, Takahashi N
- Issue date: 2016 Aug
- Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells.
- Authors: Morris DR, Ding Y, Ricks TK, Gullapalli A, Wolfe BL, Trejo J
- Issue date: 2006 Jan 1
- Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages.
- Authors: Budai MM, Varga A, Milesz S, Tőzsér J, Benkő S
- Issue date: 2013 Dec