title: Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes.
abstract: Several lines of evidence have implicated activated protein C (APC) to be an endogenous inhibitor of the inflammatory septic cascade. APC may exhibit direct anti-inflammatory properties, independent of its antithrombotic effects. Chemokines influence the interaction of monocytes at the endothelium during infection and sepsis and are involved in the molecular events leading to an adverse and lethal outcome of sepsis. Defining regulatory mechanisms on the monocytic release profile of the proinflammatory C-C chemokines macrophage inflammatory protein-1-alpha (MIP-1-alpha) and monocyte chemoattractant protein-1 (MCP-1) might have therapeutic implications for the treatment of sepsis. We established a monocytic cell model of inflammation by the addition of lipopolysaccharide (LPS) and examined the effect of human APC on LPS-stimulated chemokine release from the monocytic cell line THP-1. We found that human APC in supra-physiological concentrations of 2.5-10 microg/ml inhibited the LPS-induced release of the chemokines MIP-1-alpha and MCP-1, as measured by enzyme-linked immunosorbent assays (ELISA) at 6 up to 24 h. In addition to experiments on THP-1 cells, recombinant human APC in concentrations of 50 ng/ml was found to have an inhibiting effect on the release of MIP-1-alpha from freshly isolated mononuclear cells of septic patients. The ability of APC to decrease the release of the C-C chemokine MIP-1-alpha from the monocytic cell line THP-1 and from human monocytes may identify a novel immunomodulatory pathway by which APC exerts its anti-inflammatory action and may contribute to control the inflammatory response in sepsis.
authors.affiliation: 1st Department of Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. martina.brueckmann@med.ma.uni-heidelberg.de
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckmann
authors.forename: Ursula
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Lothar
authors.initials: L
authors.lastname: De Rossi
authors.forename: Hans Martin
authors.initials: HM
authors.lastname: Weiler
authors.forename: Volker
authors.initials: V
authors.lastname: Liebe
authors.forename: Siegfried
authors.initials: S
authors.lastname: Lang
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Kaden
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Karl K
authors.initials: KK
authors.lastname: Haase
authors.forename: Guenter
authors.initials: G
authors.lastname: Huhle
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D054407:Chemokine CCL4; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy
chemical_list: D000890:Anti-Infective Agents; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated