title: Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF-kappaB pathway.
abstract: OBJECTIVE
  Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Ethanol (EtOH) reduces host defence systems, including cell adhesion. However, well-known side effects of EtOH limit its clinical use as an anti-inflammatory drug. Instead, ethyl pyruvate (EtP) may represent a better alternative. Here, we compared effects of EtP and EtOH on neutrophil recruitment and activation of human umbilical vein endothelial cells (HUVECs).
  
  
  METHODS
  Adhesion of neutrophils to HUVEC monolayers, surface expression of intercellular cell adhesion molecule, E-selectin, vascular cell adhesion molecule, release of interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) from HUVECs were assessed as well as translocation of interleukin-1 receptor-associated kinase (IRAK-1), the nuclear factor-kappa B (NF-kappaB) subunits p50, p65 and IkappaB-alpha. NF-kappaB activation was analysed with a luciferase reporter plasmid. Cells were stimulated with IL-1beta, lipopolysaccharide (LPS) or tumour necrosis factor-alpha.
  
  
  RESULTS
  EtP was several-fold more potent than EtOH in reducing adhesion of neutrophils to activated HUVECs, generation of IL-8 or G-CSF and surface expression of the adhesion molecules. This last reaction was decreased by EtP even when added after cytokines or LPS. Translocation of IRAK-1, IkappaBalpha and the NF-kappaB p65 subunit to the HUVEC nucleus was inhibited by EtP for all stimuli, whereas the diminished p50 translocation was stimulus specific. When p65 was constitutively expressed in Cos7 cells, stimulation of an NF-kappaB-dependent reporter gene was not affected by EtP, suggesting that EtP acted upstream of gene activation.
  
  
  CONCLUSIONS
  EtP impedes adhesive, secretory and signalling events typical of the early inflammatory response in endothelial cells, suggesting EtP as a possible treatment for acute inflammatory conditions.
authors.affiliation: Center for Inflammation and Hematology Research at Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. anne-sofie.johannson@ki.se
authors.forename: A-S
authors.initials: AS
authors.lastname: Johansson
authors.forename: K
authors.initials: K
authors.lastname: Johansson-Haque
authors.forename: S
authors.initials: S
authors.lastname: Okret
authors.forename: J
authors.initials: J
authors.lastname: Palmblad
mesh_terms: D000818:Animals; D015415:Biomarkers; D019556:COS Cells; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D019040:E-Selectin / Q000096:biosynthesis; D042783:Endothelial Cells / Q000473:pathology*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D011773:Pyruvates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D019040:E-Selectin; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate; D016179:Granulocyte Colony-Stimulating Factor; D053592:Interleukin-1 Receptor-Associated Kinases