The Role of IL-6 in Inflammatory Aortic Aneurysmal Diseases
| dc.contributor.advisor | Fujise, Ken | |
| dc.contributor.committeeMember | Brasier, Allan R | |
| dc.contributor.committeeMember | Tilton, Ronald G | |
| dc.contributor.committeeMember | Milewicz, Dianna M | |
| dc.contributor.committeeMember | Vargas, Gracie | |
| dc.contributor.committeeMember | Wakamiya, Maki | |
| dc.creator | Ju, Xiaoxi 1984- | |
| dc.date.accessioned | 2016-11-14T15:22:55Z | |
| dc.date.available | 2016-11-14T15:22:55Z | |
| dc.date.created | 2012-08 | |
| dc.date.submitted | August 2012 | |
| dc.date.updated | 2016-11-14T15:22:55Z | |
| dc.description.abstract | Interleukin-6 (IL-6), a member of a superfamily of cardioactive cytokines, has been identified as an independent biomarker of vascular diseases including atherosclerosis and aortic aneurysms. Local vascular IL-6 secretion can be induced by dysregulated angiotensin II (Ang II) signaling, producing leukocyte infiltration that results in life-threatening aortic aneurysms and dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. In this study, we employed two experimental animal models to study the role of IL-6 activation in the development and progression of aortic aneurysms. In an Ang II-treated C57BL/6 mice model, we tested the relationship of IL-6 signaling with Th17-induced inflammation in the formation of Ang II-induced aortic dissections. We found that Ang II infusion induced aortic dissections and CD4+-interleukin 17A (IL-17A)-expressing, Th17 cell accumulation in C57BL/6 mice. IL-6-deficient mice showed blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections, suggesting the importance of IL-6 signaling in inducing Th17-mediated aneurysmal progression. We further showed the pathological roles of Th17 lymphocytes by depleting Th17 by IL-17A neutralization or genetic mutation and showed decreased aortic chemokine MCP-1 production and macrophage recruitment, leading to a reduction in aortic dissections. We also established clinical relevance by showing increased Th17 infiltration into the aortic adventitial-medial border in patients with ascending aortic dissections. These findings indicate that IL-6 signaling converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating vascular inflammation and aortic dissections. In another mouse model with spontaneous aortic aneurysms due to Marfan Syndrome (MFS) caused by Fbn-1 gene mutation (mgR homozygotes), we also reported elevated IL-6 signaling and increased macrophage recruitment in ascending aneurysmal tissues. To study the role of IL-6 signaling, we generated mgR homozygotes with IL-6 deficiency (DKOs), which showed reduction in aneurysmal dilation at late stage of disease with unaffected survival rate. Moreover, we reported that IL-6 deficiency led to decreased ECM degradation that is associated with reduced levels of local MMPs. These findings suggests the activation of IL-6-mediated inflammatory signaling contributed to aneurysmal progression in MFS through recruitment of leukocytes and stimulation of MMP expression, thus aggravating ECM degradation and vascular remodeling. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/2152.3/828 | |
| dc.subject | Interleukin-6 | |
| dc.subject | Aortic aneurysms | |
| dc.subject | Aortic dissections | |
| dc.subject | Angiotensin II | |
| dc.subject | Th17 | |
| dc.subject | marfan syndrome | |
| dc.title | The Role of IL-6 in Inflammatory Aortic Aneurysmal Diseases | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Biochemistry and Molecular Biology | |
| thesis.degree.discipline | Cell Biology and Molecular Biology | |
| thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Biochemistry and Molecular Biology (Doctoral) |