title: A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells.
abstract: OBJECTIVE
  Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation, endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma inflammatory response in human microvascular endothelial cells (HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPARgamma) agonist, rosiglitazone (RGZ).
  
  
  RESULTS
  TNFalpha and IFNgamma, mainly when combined, stimulate IFNgamma-inducible protein of 10 kDa (IP10) and fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNFalpha and IFNgamma stimulation of IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK activation.
  
  
  CONCLUSIONS
  Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses.
authors.affiliation: Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Lombardi
authors.forename: Giulia
authors.initials: G
authors.lastname: Cantini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Piscitelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Gelmini
authors.forename: Michela
authors.initials: M
authors.lastname: Francalanci
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mello
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ceni
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varano
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Mario
authors.initials: M
authors.lastname: Rotondi
authors.forename: Andrea
authors.initials: A
authors.lastname: Galli
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases