| First Author | Braach N | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 2 | Pages | e89422 |
| PubMed ID | 24586767 | Mgi Jnum | J:213828 |
| Mgi Id | MGI:5586640 | Doi | 10.1371/journal.pone.0089422 |
| Citation | Braach N, et al. (2014) RAGE controls activation and anti-inflammatory signalling of protein C. PLoS One 9(2):e89422 |
| abstractText | AIMS: The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-kappaB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C. 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 TNFalpha-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 microg/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 TNFalpha-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, TNFalpha-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. CONCLUSION: RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM. |
