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Functional Toll-like receptor 4 mutations modulate the response to fibrinogen
Conrad P Hodgkinson1, Kunal Patel, Shu Ye
1Clinical Pharmacology, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London, UK. c.hodgkinson@qmul.ac.uk
Thrombosis and Haemostasis
|August 12, 2008
Summary
Fibrinogen activates the Toll-like receptor 4 (TLR4) pathway, promoting inflammatory protein synthesis. This interaction explains fibrinogen's role in atherosclerosis and inflammatory responses, even with certain TLR4 mutations.
Area of Science:
- Immunology
- Molecular Biology
- Cardiovascular Research
Background:
- Fibrinogen is linked to atherosclerosis, potentially through activating the lipopolysaccharide (LPS) receptor, Toll-like receptor 4 (TLR4).
- The specific signaling pathway between fibrinogen and TLR4 is not well understood.
Purpose of the Study:
- To characterize the fibrinogen-TLR4 signaling pathway.
- To investigate how fibrinogen influences inflammatory protein expression via TLR4.
- To examine the effect of common TLR4 mutations on fibrinogen-induced signaling.
Main Methods:
- Stimulation of human macrophages and HEK293-CD14-MD2 cells expressing TLR4 with fibrinogen.
- Analysis of cytokine expression (IL-6, TNF-alpha, IL-8), kinase phosphorylation (ERK, p38alpha, JNK), and transcription factor activation (NFkappaB, Elk-1, AP-1).
- Assessment of promoter activity for inflammatory genes (MMP1, MMP9, MCP-1) and evaluation of fibrinogen's effects on polymorphic TLR4 variants (D299G, T399I).
Main Results:
- Fibrinogen stimulated interleukin-6 (IL-6) expression and ERK phosphorylation in human macrophages.
- In TLR4-expressing cells, fibrinogen robustly activated ERK1, p38alpha, JNK, and transcription factors NFkappaB, Elk-1, and AP-1.
- This led to pro-inflammatory responses, including IL-6 and TNF-alpha synthesis and increased promoter activity for IL-8, MMP1, MMP9, and MCP-1.
- Fibrinogen markedly enhanced the activation of kinases, transcription factors, cytokine synthesis, and promoter activity in cells with polymorphic TLR4 variants, unlike LPS.
Conclusions:
- Fibrinogen directly activates Toll-like receptor 4 (TLR4).
- This activation triggers a pro-inflammatory signaling cascade, leading to the synthesis of key inflammatory mediators.
- The study elucidates a mechanism by which fibrinogen contributes to inflammatory protein expression and atherosclerosis, highlighting the role of TLR4 activation.
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