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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hodgkinson, CP; Patel, K; Ye, S

Published Date

  • August 2008

Published In

Volume / Issue

  • 100 / 2

Start / End Page

  • 301 - 307

PubMed ID

  • 18690351

Pubmed Central ID

  • 18690351

International Standard Serial Number (ISSN)

  • 0340-6245


  • eng

Conference Location

  • Germany