title: Interleukin-6 Receptor Inhibition Prevents Descending Thoracic Aortic Aneurysm Formation.
abstract: BACKGROUND
  Thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA) represent related but distinct disease processes. Interleukin-6 (IL-6) is known to be significantly upregulated in human TAA and AAA. We hypothesize that loss of IL-6 is protective in experimental TAA and AAA.
  
  
  METHODS
  Murine TAAs or AAAs were created using a novel model in C57/B6 mice by treating the intact aorta with elastase. Cytokine profiles were analyzed with antibody arrays (n = 5 per group). Separately, to determine the role of IL-6, thoracic (n = 7) or abdominal (n = 7) aortas of wild type mice and IL-6 knockout (KO) mice were treated with elastase. Additionally, thoracic animals treated with either the IL-6 receptor antagonist tocilizumab (n = 8) or vehicle (n = 5). Finally, human TAA and AAA were analyzed with human cytokine array.
  
  
  RESULTS
  Elastase treatment of thoracic aortas yielded dilation of 86.8% ± 9.6%, and abdominal aortas produced dilation of 85.6% ± 16.2%. Murine IL-6, CXCL13, and matrix metalloproteinase-9 were significantly elevated in TAA compared with AAA (p = 0.004, 0.028, and 0.001, respectively). The IL-6KO mice demonstrated significantly smaller TAA size relative to wild type mice (wild type 100.1% versus IL-6KO 76.5%, p = 0.04). The IL-6KO mice did not show protection from AAA (p = 0.732). Pharmacologic inhibition of IL-6 resulted in significant reduction in TAA size (tocilizumab 71.5% ± 13.2% versus vehicle 103.6% ± 20.7%, p = 0.005). Human TAA showed significantly greater IL-6 (p < 0.0001) compared with AAA and normal thoracic and abdominal aorta.
  
  
  CONCLUSIONS
  Interleukin-6 is significantly greater in both murine and human TAA compared with AAA, suggesting fundamental differences in these disease processes. Interleukin-6 receptor antagonism attenuates experimental TAA formation, indicating that IL-6 may be a potential target for human thoracic aneurysmal disease.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Pope
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: William F
authors.initials: WF
authors.lastname: Johnston
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address: ga3f@hscmail.mcc.virginia.edu.
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; C502936:tocilizumab