title: Cardiotrophin-1 induces intercellular adhesion molecule-1 expression by nuclear factor kappaB activation in human umbilical vein endothelial cells.
abstract: BACKGROUND
  In addition to elevated concentrations of cytokines, patients with congestive heart failure (CHF) show endothelial dysfunction and increased plasma concentrations of adhesion molecules like intercellular adhesion molecule-1 (ICAM-1). Furthermore, the concentration of cardiotrophin-1 (CT-1)--a cytokine of the interleukin-6 superfamily--is increased in CHF. We tested the hypothesis whether CT-1 is able to induce ICAM-1 in human umbilical vein endothelial cells (HUVEC). Furthermore we examined the signalling mechanisms of CT-1 mediated ICAM-1 expression.
  
  
  METHODS
  Confluent layers of HUVEC were incubated with increasing concentrations of CT-1 (5 to 100 ng/ml) for different periods. ICAM-1 mRNA was determined by real-time polymerase chain reaction (PCR) and ICAM-1 surface expression by fluorescence-activated cell sorter (FACS) analysis and soluble ICAM-1 (sICAM-1) in the culture supernatant by enzyme linked immunosorbent assay (ELISA). To clarify the signalling pathway of CT-1 induced ICAM-1 expression we used various inhibitors of possible signal transducing molecules, electromobility shift assay (EMSA) and Western blot analysis.
  
  
  RESULTS
  CT-1 induced ICAM-1 mRNA (1.8 +/- 0.8 fold increase compared to unstimulated cells after 6 hours) and protein (1.4 +/- 0.2 fold increase compared to unstimulated cells after 48 hours) in HUVEC in a time- and concentration-dependent manner. EMSA experiments show that CT-1 causes nuclear factor (NF) kappaB activation. Because parthenolide could inhibit CT-1 induced ICAM-1 expression NFkappaB activation is required in this pathway. CT-1 did not activate extracellular signal regulated kinases (ERK), c-Jun N-terminal kinase (JNK) and p38.
  
  
  CONCLUSIONS
  CT-1 is able to induce ICAM-1 in endothelial cells by NFkappaB activation. These results may explain in part elevated ICAM-1 concentrations in patients with CHF and endothelial dysfunction.
authors.affiliation: Department of Internal Medicine I, Friedrich-Schiller-University Jena, Jena, Germany. Michael.Fritzenwanger@med.uni-jena.de
authors.forename: Michael
authors.initials: M
authors.lastname: Fritzenwanger
authors.forename: Martin
authors.initials: M
authors.lastname: Foerster
authors.forename: Katharina
authors.initials: K
authors.lastname: Meusel
authors.forename: Christian
authors.initials: C
authors.lastname: Jung
authors.forename: Hans R
authors.initials: HR
authors.lastname: Figulla
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002070:Butadienes; D016207:Cytokines; D016328:NF-kappa B; D009570:Nitriles; D012717:Sesquiterpenes; C113580:U 0126; D018799:Intercellular Adhesion Molecule-1; C432165:pyrazolanthrone; C002669:parthenolide; C092073:cardiotrophin 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases