title: Modulatory effect of fenofibrate on endothelial production of neutrophil chemokines IL-8 and ENA-78.
abstract: OBJECTIVE
  The PPAR-alpha agonists (fibrates) are commonly used in the treatment of dyslipidemia. It has been hypothesized that the cardio-protective effects of fibrates are partially due to immunomodulatory effects. However, there is a paucity of data regarding the effect of fibrates on neutrophilic chemokines such as epithelial neutrophil activating protein (ENA-78) and interleukin (IL)-8. We investigated the influence of fenofibrate on IL-1β-stimulated production of ENA-78 and IL-8 from human endothelial cells (HUVECs).
  
  
  METHODS
  HUVECs were cultured in the presence or absence of IL-1β and fenofibrate ranging from 1-50 uM. ENA-78 and IL-8 were measured and normalized to total protein content in cell culture supernates by multiplex immunofluorescence detection. Experimental samples were measured in triplicate. Significance was set at P < 0.05 by ANOVA with correction for multiple comparisons.
  
  
  RESULTS
  Endothelial production of both ENA-78 and IL-8 was induced by the proinflammatory cytokine IL-1β. ENA-78 concentrations increased by more than 160-fold over constitutively produced ENA-78 upon IL-1β stimulation (mean ± SEM: 10,129 ± 1591 pg/mg vs. 61 ± 9.5 mg/mg; P < 0.0001). IL-8 concentrations increased by slightly over 5-fold (6145 ± 860 pg/mg vs. 1160 ± 201 pg/mg; P = 0.0003). ENA-78 protein and mRNA were significantly reduced by fenofibrate while no drug effects were observed on IL-8 production.
  
  
  CONCLUSIONS
  Fenofibrate blunts IL-1β-mediated ENA-78 production with no effect on IL-8. This represents a novel mechanism by which fenofibrate exerts anti-inflammatory effects and should be further explored.
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, AR, USA. ETPrice@uams.edu
authors.forename: Elvin Tyrone
authors.initials: ET
authors.lastname: Price
authors.forename: Gregory James
authors.initials: GJ
authors.lastname: Welder
authors.forename: Issam
authors.initials: I
authors.lastname: Zineh
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054365:Chemokine CXCL5 / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D007155:Immunologic Factors; D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D011345:Fenofibrate