title: Anti-inflammatory functions of protein C require RAGE and ICAM-1 in a stimulus-dependent manner.
abstract: By binding β 2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNF α ). In contrast to WT and Icam-1(-/-) mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE(-/-) mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC.
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Braach
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Buschmann
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pflaum
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hudalla
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Koch
authors.affiliation: Department of Surgery, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Ryschich
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Poeschl
authors.affiliation: Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: David
authors.identifier: 0000-0002-7289-1346
authors.initials: D
authors.lastname: Frommhold
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology; D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D019446:Endotoxemia / Q000473:pathology; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D011486:Protein C / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C090509:Icam1 protein, mouse; D008070:Lipopolysaccharides; D011486:Protein C; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1