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1. Cuneo, Anthony. THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES.
Degree: PhD, 2012, Temple University
Molecular and Cellular Physiology
Cardiovascular disease is the leading cause of mortality in the western world. The pro-inflammatory and pro-proliferative etiology of vascular proliferative diseases is well characterized, while much less is known about the mechanisms of anti-inflammatory and anti-proliferative processes. Interleukin-19 (IL-19) is a newly described member of the IL-10 family of anti-inflammatory interleukins, and our group was the first to discover IL-19 expression in activated, synthetic, but not quiescent, contractile human vascular smooth muscle cells (hVSMC). We also found that IL-19 is anti-inflammatory and anti-proliferative for hVSMC. IL-19 is able to reduce the abundance of COX-2, IL-1β, IL-8, and Cyclin D1 transcripts which contain AU-rich elements (ARE) in their 3'-untranslated regions (3'-UTR). IL-19 is able to reduce the abundance of HuR, a stabilizing RNA-binding protein, which we feel provides a mechanism for these effects. The overall goal of this study is to elucidate IL-19's anti-inflammatory and anti-proliferative mechanism(s) in hVSMC in the context of vascular proliferative diseases. This goal has directed our overall hypothesis: IL-19's anti-proliferative and anti-inflammatory effects in hVSMC are mediated, at least in part, by modulation of HuR abundance and translocation, resulting in decreased stability of mRNA transcripts. HuR functions through a translocation mechanism, and IL-19 is able to reduce HuR cytoplasmic abundance. IL-19 also reduces HuR phosphorylation, which is a pre-requisite for HuR translocation, possibly through a PKCα-dependent mechanism. The stability of ARE-containing transcripts is reduced with IL-19 treatment, and reducing HuR expression by siRNA has the same inhibitory effect. VSMC are important mediators in the initiation of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) is able to induce IL-19 expression in these cells. VSMC are known to express scavenger receptors that take up ox-LDL. IL-19 is able to reduce the uptake of ox-LDL and the abundance of ox-LDL induced LOX-1 and CX-CL16 scavenger receptors. Interestingly, these scavenger receptors also have ARE in their 3'-UTR. IL-19 is able to reduce ox-LDL induced HuR cytoplasmic abundance. HuR knockdown by siRNA reduces the uptake of ox-LDL by hVSMC. These data suggest that IL-19 reduced scavenger receptor abundance may be due to decreased total and cytoplasmic HuR abundance. IL-19 reduces the abundance of ox-LDL induced COX-2 expression. Taken together, these results demonstrate that IL-19 down-regulates vital steps in vascular proliferative disease processes through an HuR-dependent mechanism.
Temple University – ThesesAdvisors/Committee Members: Autieri, Michael V., Eguchi, Satoru, Haines, Dale, Houser, Steven R., Soprano, Dianne R., Wolfson, Marla R..
Subjects/Keywords: Biology, Molecular; Biology, General; Biology, Cell; Atherosclerosis; Human antigen R (HuR); Interleukin-19 (IL-19); oxidized LDL (ox-LDL); Vascular Proliferative Diseases; Vascular Smooth Muscle Cells (VSMC)
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APA (6th Edition):
Cuneo, A. (2012). THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,78032
Chicago Manual of Style (16th Edition):
Cuneo, Anthony. “THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES.” 2012. Doctoral Dissertation, Temple University. Accessed August 14, 2020. http://digital.library.temple.edu/u?/p245801coll10,78032.
MLA Handbook (7th Edition):
Cuneo, Anthony. “THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES.” 2012. Web. 14 Aug 2020.
Cuneo A. THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Aug 14]. Available from: http://digital.library.temple.edu/u?/p245801coll10,78032.
Council of Science Editors:
Cuneo A. THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,78032