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EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice
- Source :
- Blood. 125(18)
- Publication Year :
- 2014
-
Abstract
- Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow–derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses.
- Subjects :
- Lipopolysaccharides
Immunology
Receptors, Cell Surface
Biochemistry
Thrombosis and Hemostasis
Tissue factor
Mice
Interferon
hemic and lymphatic diseases
medicine
Animals
Receptor, PAR-2
Coagulation factor II receptor
Blood Coagulation
Cells, Cultured
Mice, Knockout
Endothelial protein C receptor
Innate immune system
Chemistry
Endothelial Protein C Receptor
Cell Biology
Hematology
Molecular biology
Blood Coagulation Factors
Endotoxemia
Cell biology
Mice, Inbred C57BL
Gene Expression Regulation
TLR3
TLR4
lipids (amino acids, peptides, and proteins)
Interferons
IRF8
Erratum
medicine.drug
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 125
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....f8c0f4a25c9417ae9a22a97414216c41