Potentiation of TLR4 signalling by plasmin activity.
The potential for proteases to regulate mammalian TLR signalling is controversial. We found that inhibition of extracellular serine proteases did not reduce activation of TLR4, but observed that the protease plasmin, an important fibrinolytic plasma enzyme that also exerts proinflammatory functions in monocytes, potentiated TLR2 and TLR4 signalling in RAW264.7 macrophages. Plasmin enhanced endogenous production of TNFalpha and activation of an NF-kappaB reporter plasmid. These actions were prevented by inhibition of its proteolytic activity and were not recapitulated by agonists of protease-activated receptors. These studies link fibrinolysis and TLR signalling, identifying further mechanisms potentially involved in activation of innate immunity.
Ward
Jon R
JR
Division of Genomic Medicine, University of Sheffield Medical School, University of Sheffield, Sheffield S10 2JF, UK.
Dower
Steven K
SK
Whyte
Moira K B
MK
Buttle
David J
DJ
Sabroe
Ian
I
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D017930:Genes, Reporter; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D005337:Fibrin; D010447:Peptide Hydrolases; D005341:Fibrinolysin