Mechanism of local IL-6 production and its role in accelerating vascular inflammation leading to aortic diseases

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dc.contributor.advisor Ronald Tilton en_US
dc.contributor.committeeMember Steven Weinman en_US
dc.contributor.committeeMember Michael Boulton en_US
dc.contributor.committeeMember Dianna Milewicz en_US
dc.contributor.committeeMember Darrell Carney en_US
dc.creator Brian Cuong Tieu en_US 2011 -12 -20T16 :05 :44Z 2014 -02 -19T22 :05 :49Z 2010 -09 -28 en_US 2011 -12 -20T16 :05 :44Z 2014 -02 -19T22 :05 :49Z 2008 -12 -15 en_US 2008 -12 -03 en_US
dc.identifier.other etd -12152008 -155723 en_US
dc.identifier.uri http : / /hdl .handle .net /2152 .3 /294
dc.description.abstract Vascular inflammation plays a significant role in aortic diseases and involves enhanced recruitment and local activation of circulating monocytes along with cytokine production , but the mechanisms responsible for these processes are unclear . The cytokine interleukin -6 (IL -6 ) is highly induced in aortic aneurysm and dissection and significantly increases the risk of aneurysm rupture and mortality due to cardiovascular diseases ; however , it remains unknown where and how IL -6 is produced in the vascular wall and how it contributes to disease exacerbation . Using an Ang II -infusion mouse model , we found that 6 days of subcutaneous Ang II infusion into aged C57BL /6J mice induced aortic IL -6 and MCP -1 predominantly in the tunica adventitia . Likewise , IL -6 was detected mostly in the adventitia of sporadic aortic dissections in humans . There was concomitant macrophage recruitment , adventitial expansion , and development of thoracic and suprarenal aortic aneurysms and dissections in treated wild -type mice . In contrast , no dissections were produced with infusion into IL -6 - / - or CCR2 - / - mice over the same time period along with significantly reduced inductions of aortic IL -6 and MCP -1 . Using flow cytometric quantification of aortic cellular constituents , we found that Ang II induced CCR2+ macrophage accumulation of a specific CD14hiCD11bhiF4 /80 - phenotype selectively in aortic dissections and not in aortas from IL -6 - / - mice , which were CD14loCD11bloF4 /80+ . Adoptive transfer of CCR2+ /+ monocytes into CCR2 - / - mice resulted in selective monocyte uptake into the thoracic and suprarenal aorta with restoration of IL -6 and MCP -1 secretion and increased incidence of dissection . To elucidate a source of IL -6 , we demonstrated that aortic adventitial fibroblasts (AoAFs ) highly produce IL -6 and MCP -1 and Ang II treatment increased their expression . Ang II and monocytes stimulated AoAF proliferation also . In addition , coculture of monocytes and AoAFs strongly potentiated MCP -1 and IL -6 , which differentiated monocytes to macrophages and up -regulated CD14 and CD11b as well as induced MCP -1 and MMP -9 expression . These results suggest that AoAFs are a source of IL -6 and that a leukocyte -fibroblast interaction in the aortic adventitia potentiates its production , leading to promotion of local monocyte recruitment and activation , thereby accelerating vascular inflammation , ECM remodeling and aortic destabilization . en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author . Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works . en_US
dc.subject monocytes en_US
dc.subject MCP -1 en_US
dc.subject macrophages en_US
dc.subject IL -6 en_US
dc.subject CCR2 en_US
dc.subject angiotensin II en_US
dc.subject adventitial fibroblasts en_US
dc.title Mechanism of local IL -6 production and its role in accelerating vascular inflammation leading to aortic diseases en_US
dc.type.genre dissertation en_US
dc.type.material text en_US PhD en_US Doctoral en_US The University of Texas Medical Branch en_US Human Biological Chemistry and Genetics en_US


Mechanism of local IL-6 production and its role in accelerating vascular inflammation leading to aortic diseases. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /294 .

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