Blood cells, molecules & diseases · 2014
Mechanism of tissue factor production by monocytes stimulated with neutrophil elastase.
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Kawata Jin, Aoki Manabu, Ishimaru Yasuji, Ono Tomomichi, Sagara Katsurou, Narahara Shinji, Matsmoto Tamami, Hirose Eiji, Yamaguchi Yasuo
Аннотация
BACKGROUND: Monocytes and neutrophils are activated during disseminated intravascular coagulation. Tissue factor, the main initiator of coagulation, is expressed by monocytes, while elastase is released by neutrophils.
AIMS: This study investigated tissue factor production by peripheral monocytes after stimulation with human neutrophil elastase.
METHODS: Tissue factor mRNA levels were investigated by the reverse transcriptase-polymerase chain reaction and tissue factor protein production was assessed by western blotting when monocytes were exposed to neutrophil elastase with or without preincubation using various inhibitors.
RESULTS: Neutrophil elastase upregulated tissue factor mRNA and protein levels in monocytes. Both U73122 (phospholipase C inhibitor) and TMB-8 (intracellular calcium antagonist) prevented the upregulation of tissue factor mRNA. SB203580 (p38 mitogen-activated protein kinase inhibitor) suppressed this response, but PD98059 (extracellular signal-regulated kinase inhibitor) did not. Ro-318425 (ATP-competitive and selective protein kinase C (PKC) inhibitor) and Go 6976 (inhibitor of conventional PKCs and PKCμ) blocked the upregulation of tissue factor mRNA expression. Go 6983 (broad-spectrum PKC inhibitor) and CGP 4125 (staurosporine analog) partially attenuated it, as did a PKC theta/delta inhibitor.
CONCLUSIONS: Neutrophil elastase mainly enhances tissue factor production by monocytes via the phospholipase C/conventional PKC/p38 MAPK pathway, although a novel PKC is also involved.
AIMS: This study investigated tissue factor production by peripheral monocytes after stimulation with human neutrophil elastase.
METHODS: Tissue factor mRNA levels were investigated by the reverse transcriptase-polymerase chain reaction and tissue factor protein production was assessed by western blotting when monocytes were exposed to neutrophil elastase with or without preincubation using various inhibitors.
RESULTS: Neutrophil elastase upregulated tissue factor mRNA and protein levels in monocytes. Both U73122 (phospholipase C inhibitor) and TMB-8 (intracellular calcium antagonist) prevented the upregulation of tissue factor mRNA. SB203580 (p38 mitogen-activated protein kinase inhibitor) suppressed this response, but PD98059 (extracellular signal-regulated kinase inhibitor) did not. Ro-318425 (ATP-competitive and selective protein kinase C (PKC) inhibitor) and Go 6976 (inhibitor of conventional PKCs and PKCμ) blocked the upregulation of tissue factor mRNA expression. Go 6983 (broad-spectrum PKC inhibitor) and CGP 4125 (staurosporine analog) partially attenuated it, as did a PKC theta/delta inhibitor.
CONCLUSIONS: Neutrophil elastase mainly enhances tissue factor production by monocytes via the phospholipase C/conventional PKC/p38 MAPK pathway, although a novel PKC is also involved.
Предметные рубрики MeSH
Calcium Channel BlockersCarbazolesEnzyme InhibitorsEstrenesFlavonoidsGallic AcidGene Expression RegulationHumansImidazolesIndolesLeukocyte ElastaseMaleimidesMonocytesPrimary Cell CultureProtein Kinase CProtein Kinase InhibitorsPyridinesPyrrolidinonesRNA, MessengerSignal TransductionThromboplastinType C Phospholipasesp38 Mitogen-Activated Protein Kinases