title: Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients.
abstract: BACKGROUND
  Vascular access failure is the main cause of morbidity in hemodialysis patients. Stenosis of the arteriovenous fistula (AVF) is similar histologically to atherosclerosis. Recent studies showed that interleukin 6 (IL-6) has a key role in the pathogenesis of atherosclerosis by binding 2 specific receptors, gp80 and gp130. When activated, gp130 interacts with a tyrosine kinase, Janus kinase (JAK2), which then activates a transcription factor, signal transducers and activators of transcription (STAT3), directly turning on several proinflammatory genes. The aim of this study is to evaluate gp130 expression and JAK2/STAT3 activation within stenotic AVFs.
  
  
  METHODS
  44 patients undergoing surgery for AVF creation were enrolled; 10 of them had AVF failure with histologically proven AVF stenosis (wall-lumen ratio > 1). A venous fragment of the AVFs was collected during creation and revision of the vascular access. gp130 and gp80 expression, as well as JAK/STAT activation, were evaluated by means of confocal microscopy. Peripheral-blood mononuclear cells were isolated at the time of AVF creation and revision.
  
  
  RESULTS
  gp130 protein expression, barely detectable in native AVFs, was strikingly increased within the venous branch of stenotic AVFs. The signaling subunit of the IL-6 receptor broadly colocalized with gp80, the IL-6-binding subunit. gp130-expressing cells were mainly CD34(+), suggesting that this receptor is expressed primarily by neovasculature endothelial cells. At the same time, a significant increase in phosphorylation of JAK2/STAT3 was observed in endothelial cells of stenotic AVFs. Interestingly, peripheral-blood mononuclear cells isolated at the time of AVF failure presented strikingly greater IL-6 expression compared with dialysis age-matched controls.
  
  
  CONCLUSIONS
  IL-6 receptor activation may have a role in the pathogenesis of AVF failure in hemodialysis patients and may represent a potential therapeutic target in this setting.
authors.affiliation: Department of Emergency and Transplantation, Division of Nephrology, Dialysis and Transplantation, University of Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Marrone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pertosa
authors.forename: Simona
authors.initials: S
authors.lastname: Simone
authors.forename: Antonella
authors.initials: A
authors.lastname: Loverre
authors.forename: Carmen
authors.initials: C
authors.lastname: Capobianco
authors.forename: Mario
authors.initials: M
authors.lastname: Cifarelli
authors.forename: Bruno
authors.initials: B
authors.lastname: Memoli
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Schena
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
mesh_terms: D000328:Adult; D000368:Aged; D001164:Arteriovenous Fistula / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D003251:Constriction, Pathologic; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008875:Middle Aged; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000378:metabolism / Q000502:physiology; D006435:Renal Dialysis; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130