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The intersubject variability of tissue factor mRNA production in human monocytes: relation with the toll-like receptor 4
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.
2007 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 3, 407-413 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Tissue factor (TF) is known as the primary initiator of blood coagulation. Previous studies have suggested a considerable variation in the monocytic lipopolysaccharide (LPS) stimulated TF antigen levels and procoagulant activities between different individuals. Our aim with the present study was to investigate the replicability of LPS induced TF mRNA production in a series of standardised experiments with the purpose to identify putative factors influencing the TF high and low response. Results: A constant and reproducible production of LPS induced TF mRNA was identified in five high responders and three low responders (out of 42 individuals) and followed-up in three subsequent experiments performed over 2 years. The LPS induced TF mRNA production correlated with the corresponding expressions of interleukin-8, tumor necrosis factor-alfa and interleukin-1 beta, indicating a common pathway with the TF high and low response. A strong and significant correlation between the LPS induced TF and toll-like receptor 4 mRNA expressions was subsequently identified and replicated. Conclusions: We demonstrated a high and low responder phenomenon of LPS induced TF mRNA in human monocytes. The production of toll-like receptor 4 mRNA was significantly enhanced in TF high responders.

Place, publisher, year, edition, pages
2007. Vol. 120, no 3, 407-413 p.
Keyword [en]
Cytokine, Interleukin 1, Tumor necrosis factor, Interleukin 8, Lipopolysaccharide, Blood coagulation, Monocyte, Human, Tissue factor, Variability, Cardiovascular disease
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94460DOI: 10.1016/j.thromres.2006.10.008ISI: 000247762600013PubMedID: 17157899OAI: oai:DiVA.org:uu-94460DiVA: diva2:168308
Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2011-01-29Bibliographically approved
In thesis
1. Tissue Factor and CD40 Ligand: Markers for the Interplay of Coagulation and Inflammation in the Acute Coronary Syndrome
Open this publication in new window or tab >>Tissue Factor and CD40 Ligand: Markers for the Interplay of Coagulation and Inflammation in the Acute Coronary Syndrome
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

BACKGROUND: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. CD40 ligand is another membrane molecule, which ligates to cell types associated with atherosclerotic plaques thereby mediating intraplaque inflammation and weakening of the fibrous cap. Acute coronary syndrome (ACS) is a multi-factorial disease in which TF and CD40 ligand have prominent roles. Single nucleotide poly-morphisms (SNPs) in the TF and CD40 ligand genes may influence the development, pro-gression and outcome in ACS. AIM: The aim of this thesis was to investigate the genetic and molecular control of TF expression in healthy individuals and in patients with ACS. More-over, the aim was to investigate whether SNPs in the TF and CD40L genes respectively were associated with risk and outcome in ACS and / or with plasma concentrations of these pro-teins. RESULTS: A real-time PCR method that allowed sensitive and dynamic quantification of TF mRNA was established and used for the identification of a high and low response phe-nomenon of TF mRNA. The TF high and low response correlated with the expression of toll-like receptor 4 (TLR-4) thus linking TF to innate immunity in a novel fashion. Investigation of several SNPs in the TF and CD40L genes led to the identification of the 5466 A>G in the TF gene and the -3459 A>G SNP in the CD40L gene. The 5466 G allele was associated with cardiovascular death in patients with ACS and increased TF procoagulant activity in human monocytes, which explained the clinical association. The -3459 G allele regulated the produc-tion of soluble CD40L but was not related with patient outcome. Soluble CD40L levels above median were associated with the risk of MI in patients with ACS. A prolonged treatment with dalteparin was more efficient in patients presenting with high levels of sCD40L, which further supports sCD40L as a marker of a prothrombotic state. CONCLUSIONS: The results of this thesis adds to our current knowledge of factors influencing TF expression and activity by demonstrating the effects of TF gene variants, cell signalling molecules, CD40 ligand protein and gene variation. All of these effects have the potential to modify the risk of development, progression and outcome in the acute coronary syndrome and exemplify the interplay between coagulation and inflammation, in which both TF and CD40 ligand are active.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 149
Keyword
Molecular medicine, tissue factor, CD40 ligand, gene expression, single nucleotide polymorphism, acute coronary syndrome, myocardial infarction, coagulation, inflammation, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-6841 (URN)91-554-6558-7 (ISBN)
Public defence
2006-05-23, Ebba Enghoffsalen, Ingång 50, Uppsala Akademiska Sjukhus, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-05-02 Created: 2006-05-02Bibliographically approved

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