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RAGE controls activation and anti-inflammatory signalling of protein C.
- Source :
-
PloS one [PLoS One] 2014 Feb 24; Vol. 9 (2), pp. e89422. Date of Electronic Publication: 2014 Feb 24 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Aims: The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C.<br />Methods and Results: We analyzed the effect of protein C on leukocyte adhesion and transmigration in WT- and RAGE-deficient mice using intravital microscopy of cremaster muscle venules during trauma- and TNFα-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 µg/kg/h) treatment significantly inhibited leukocyte adhesion in WT mice in these inflammation models. The impaired leukocyte adhesion after trauma-induced inflammation in RAGE knockout mice could not be further reduced by PC and aPC. After TNFα-stimulation, however, aPC but not PC treatment effectively blocked leukocyte adhesion in these mice. Consequently, we asked whether RAGE is involved in PC activation. Since RAGE-deficient mice and endothelial cells showed insufficient PC activation, and since thrombomodulin (TM) and endothelial protein C receptor (EPCR) are reduced on the mRNA and protein level in RAGE deficient endothelial cells, an involvement of RAGE in TM-EPCR-dependent PC activation is likely. Moreover, TNFα-induced activation of MAPK and upregulation of ICAM-1 and VCAM-1 are reduced both in response to aPC treatment and in the absence of RAGE. Thus, there seems to be interplay of the RAGE and the PC pathway in inflammation.<br />Conclusion: RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.
- Subjects :
- Animals
Cell Adhesion genetics
Endothelial Cells metabolism
Endothelial Protein C Receptor
Humans
Inflammation genetics
Inflammation metabolism
Intercellular Adhesion Molecule-1 genetics
Intercellular Adhesion Molecule-1 metabolism
Leukocytes metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein C genetics
Receptor for Advanced Glycation End Products
Receptors, Cell Surface genetics
Receptors, Immunologic genetics
Thrombomodulin genetics
Thrombomodulin metabolism
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
Up-Regulation genetics
Vascular Cell Adhesion Molecule-1 genetics
Vascular Cell Adhesion Molecule-1 metabolism
Anti-Inflammatory Agents metabolism
Protein C metabolism
Receptors, Cell Surface metabolism
Receptors, Immunologic metabolism
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24586767
- Full Text :
- https://doi.org/10.1371/journal.pone.0089422