Functional Toll-like receptor 4 mutations modulate the response to fibrinogen

Conrad P. Hodgkinson; Kunal Patel; Shu Ye

doi:10.1160/TH08-03-0179

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(02): 301-307
DOI: 10.1160/TH08-03-0179

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Functional Toll-like receptor 4 mutations modulate the response to fibrinogen

Conrad P. Hodgkinson

¹Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, London, UK

,

Kunal Patel

¹Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, London, UK

,

Shu Ye

¹Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, London, UK

› Author Affiliations

Abstract

Summary

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 un-characterised. 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, p38α and JNK and activated transcription factors NFκB, Elk-1 and AP-1 (activator protein-1).The net effect of this signaling pathway was a pro-inflammatory response characterised by IL6 and TNFα 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.

Keywords

Signal transduction - protein kinases/phosphatases - transcription factors - inflammation

Full Text

References

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