title: Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice.
abstract: OBJECTIVE
  Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice.
  
  
  RESULTS
  Ang II infusion induced aortic dissections and CD4(+)-interleukin 17A (IL-17A)-expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6(-/-) mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II-infused mice with IL-17A-neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A-neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II-mediated aortic dissections occurred independent of blood pressure changes.
  
  
  CONCLUSIONS
  Our results indicate that the IL-6-signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Ju
authors.forename: Talha
authors.initials: T
authors.lastname: Ijaz
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Sutapa
authors.initials: S
authors.lastname: Ray
authors.forename: Wanda
authors.initials: W
authors.lastname: Lejeune
authors.forename: Chang
authors.initials: C
authors.lastname: Lee
authors.forename: Adrian
authors.initials: A
authors.lastname: Recinos
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
mesh_terms: D000784:Aortic Dissection / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000804:Angiotensin II; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D001011:Aorta / Q000276:immunology* / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D001794:Blood Pressure; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D046509:Tissue Culture Techniques
chemical_list: D057134:Antibodies, Neutralizing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C098680:Il17a protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000804:Angiotensin II
keywords: T-lymphocytes, helper; angiotensin II; aortic dissection, familial; inflammation; interleukin-6; vascular inflammation