title: RAGE controls activation and anti-inflammatory signalling of protein C.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Braach
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Frommhold
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Buschmann
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pflaum
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Koch
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hudalla
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Staudacher
authors.affiliation: Department of Clinical Chemistry and Biochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Chemistry and Biochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Poeschl
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D000074283:Endothelial Protein C Receptor; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000074283:Endothelial Protein C Receptor; C080248:Procr protein, mouse; D011486:Protein C; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1