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Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
2008 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, 986-994 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: P-selectin and CD40L expressed by activated platelets induce tissue factor (TF) and inflammatory cytokines in monocytes, but little is known of the cellular signaling pathways involved. The anti-inflammatory cytokine IL10 reduces atherosclerotic plaque formation. OBJECTIVES: To evaluate the importance of P-selectin upon platelet-monocyte aggregate (PMA) formation in thrombin receptor activator peptide (TRAP) stimulated whole blood, the P-selectin-P-selectin glycoprotein ligand (PSGL)-1-induced cellular signaling pathway, and the effects of IL10 on these functions. METHODS: TF, IL8, and monocyte chemotactic protein-1 (MCP-1) production, PMAs and phosphorylation of Lyn were analyzed in whole blood, purified monocytes, and vitamin D(3)-differentiated U-937 cells stimulated with TRAP or P-selectin with or without IL10. Anti-P-selectin or anti-CD40L antibodies (Abs), Src-kinases inhibitors, SU6656 or PP2, were added in some experiments. RESULTS: TRAP and P-selectin increased TF, IL8, and MCP-1 mRNA in whole blood and purified monocytes. Anti-P-selectin Ab reduced TRAP-induced PMA formation by 80 +/- 2% (P = 0.001) and production of TF (P = 0.04) and IL8 (P = 0.01). IL10 and SU6656 had no effect on PMA formation, although both significantly reduced TF (P = 0.002 and P = 0.02) and IL8 (P = 0.009 and P = 0.001) mRNA upon TRAP and P-selectin stimulation. Induced Lyn phosphorylation in monocytes was diminished by SU6656 (P = 0.02), anti-P-selectin Ab (P = 0.02), and IL10 (P = 0.03) upon TRAP or P-selectin stimulation. These results were confirmed in the vitamin D(3)-differentiated U-937 cells. CONCLUSIONS: The formation of PMAs in whole blood was P-selectin-dependent in the long term. P-selectin-PSGL-1-induced TF and IL8 expression through Lyn phosphorylation, and part of the inhibitory effect of IL10 depends on reduced phosphorylation.

Place, publisher, year, edition, pages
2008. Vol. 6, no 6, 986-994 p.
Keyword [en]
IL8, IL10, Lyn, platelet-monocyte aggregates, P-selectin, tissue factor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97124DOI: 10.1111/j.1538-7836.2008.02956.xISI: 000255943600013PubMedID: 18363812OAI: oai:DiVA.org:uu-97124DiVA: diva2:171923
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2012-07-12Bibliographically approved
In thesis
1. Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
Open this publication in new window or tab >>Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs).

In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes.

Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 341
Keyword
Internal medicine, Myocardial infarction, Coagulation, Platelet-monocyte aggregates, Tissue factor, Thrombin inhibition, Invärtesmedicin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-8669 (URN)978-91-554-7177-4 (ISBN)
Public defence
2008-05-17, Enghoffsalen, Ingång 50 bv, Uppsala Universitets Sjukhus, Uppsala, 10:00
Opponent
Supervisors
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2012-03-06Bibliographically approved

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Christersson, ChristinaJohnell, MatildaSiegbahn, Agneta

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