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.
Hodgkinson
Conrad P
CP
Clinical Pharmacology, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London, UK. c.hodgkinson@qmul.ac.uk
Patel
Kunal
K
Ye
Shu
S
D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017354:Point Mutation; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
C494112:ELK1 protein, human; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D050807:ets-Domain Protein Elk-1; D005340:Fibrinogen; D048031:JNK Mitogen-Activated Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3