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http://hdl.handle.net/11375/18057
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DC Field | Value | Language |
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dc.contributor.advisor | Trigatti, Bernardo | - |
dc.contributor.author | Dadoo, Omid | - |
dc.date.accessioned | 2015-09-24T14:40:21Z | - |
dc.date.available | 2015-09-24T14:40:21Z | - |
dc.date.issued | 2015 | - |
dc.identifier.uri | http://hdl.handle.net/11375/18057 | - |
dc.description.abstract | Interleukin-15 is a well known pro-inflammatory cytokine which regulates many activities of immune cells including macrophages, CD8 T, natural killer, and natural killer T cells. All these cell types have been shown to contribute to atherogenesis. Here we report that Interleukin-15 plays a key role in the progression of atherosclerosis in both aortic sinus and coronary arteries. Mice lacking Interleukine-15 had lower levels of atherosclerosis while mice overexpressing Interleukin-15 had increased plaque size. We also showed that this effect on atherosclerosis is partially independent of natural killer, natural killer T, and CD8 T cells. Immunodepletion of NK1.1+ cells led to less atherosclerosis in IL-15+/- ApoE-/- compared with IL-15+/+ ApoE-/- mice. Furthermore the absence of IL-15 in IL15-/- ApoE-/- mice resulted in lower expression of MCP-1 and less presence of CD11b+ cells in plaques compared with ApoE-/- control mice. In addition, in vitro treatment of macrophages with Interleukin-15 increased the expression of inflammatory cytokines, while a soluble Interleukin-15 receptor α suppressed the pro-inflammatory effects of Interleukin-15. These findings are consistent with others’ findings that Interleukine-15 affects macrophages through Interleukin-15 receptor α. To further examine this in vivo, we transplanted bone marrow from wild-type or Interleukin-15 receptor α knockout mice into LDLR-/- recipients. Mice lacking Interleukin-15 receptor α in their bone marrow derived cells developed smaller plaques. Also, we confirmed that Interleukin-15’s pro-inflammatory effect in macrophages isolated from Interleukin-15 receptor α knockout mice was partially suppressed, in comparison with macrophages isolated from wild-type mice. It has been shown that the absence of HDL receptor (SR-BI) and ApoE in SR-BI/ApoE dKO mice leads to severe coronary artery atherosclerosis and consequently heart attack. We demonstrated that a lack of Interleukin-15 in IL-15/SR-BI/ApoE tKO mice, improved the survival of these mice compared with SR-BI/ApoE dKO control animals and also reduced the levels of atherosclerosis both in aortic sinus and coronary arteries. In conclusion, these findings indicate that Interleukin-15 promotes atherosclerosis through multiple cellular and molecular mechanisms including monocyte/macrophage activation and survival/maturation of natural killer and CD8 T cells. | en_US |
dc.language.iso | en | en_US |
dc.title | CELLULAR AND MOLECULAR MECHANISMS BY WHICH INTERLEUKIN-15 CONTRIBUTES TO ATHEROSCLEROSIS | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Biochemistry and Biomedical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
dc.description.layabstract | Cardiovascular diseases (CVD) are leading causes of death in Canada and among different types of CVD’s, atherosclerosis is the most dominant type. During the progression of this disease, immune cells and cholesterol carrying lipoproteins trespass the wall of arteries where, immune cells such as macrophages engulf cholesterol resulting in narrowing of lumens of arteries. Studies show that elements of our immune system together with other factors such as the levels of lipids in circulation, determine the severity of atherosclerosis development and consequently the occurrence of heart attack and stroke. Our findings demonstrate that Interleukin-15, a protein which regulates many aspects of immune system, plays an important role in atherosclerosis development. Using a variety of biological approaches, we have shown less atherosclerotic plaques in the absence of Interleukin-15 in mouse models, suggesting that this protein can be potentially targeted therapeutically in patients who have high levels of Interleukin-15. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Dadoo O- PhD Thesis- June 15 2015.pdf | 3.23 MB | Adobe PDF | View/Open |
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