Functional Toll-like receptor 4 mutations modulate the response to fibrinogen.
Fibrinogen has been implicated in atherosclerosis; in part by activating the lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4). The fibrinogen-TLR4 signalling pathway remains uncharacterised. In human macrophages fibrinogen stimulated interleukin (IL)6 expression and ERK (extracellular signal-related kinase) phosphorylation. In HEK293-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk-1 and AP-1 (activator protein-1). The net effect of this signalling pathway was a pro-inflammatory response characterised by IL6 and TNFalpha synthesis and increased IL8, matrix metalloproteinase (MMP)1, MMP9, and MCP-1 promoter activity. Two common TLR4 mutations, D299G and T399I, render the receptor LPS hyporesponsive. The effect of fibrinogen on polymorphic variant TLR4s was markedly different; enhancing activation of kinases, transcription factors, cytokine synthesis and promoter activity. This study indicates that fibrinogen activates TLR4, explaining how fibrinogen promotes inflammatory protein expression.
Duke Scholars
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Related Subject Headings
- ets-Domain Protein Elk-1
- Transfection
- Transcription Factor AP-1
- Toll-Like Receptor 4
- Signal Transduction
- Point Mutation
- NF-kappa B
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 14
- Macrophages
Citation
Published In
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- ets-Domain Protein Elk-1
- Transfection
- Transcription Factor AP-1
- Toll-Like Receptor 4
- Signal Transduction
- Point Mutation
- NF-kappa B
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 14
- Macrophages