BACKGROUND: Atherosclerotic vascular disease is a significant medical and socioeconomic problem and contributes to mortality in multiple diseases including myocardial infarction (MI), stroke, renal failure, and peripheral vascular disease. Atherosclerosis, as well as other vascular diseases including post-intervention restenosis and allograft vasculopathy, is known to be driven by chronic inflammation and, consequently, pro- and anti-inflammatory cell signaling molecules have been an important target of cardiovascular research. Interleukin (IL)-19 is a recently discovered member of the IL-10 family of anti-inflammatory cytokines. IL-19 is expressed in injured vascular cells, including vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), where it exerts an anti-inflammatory effect. In VSMCs, IL-19 signaling results in inhibition of proliferation, migration, spreading, production of reactive oxygen species (ROSs), and expression of pro-inflammatory genes. In ECs, IL-19 signaling is pro-angiogenic and results in increased EC proliferation, migration, and spreading. AIMS and HYPOTHESIS: The goal of the present study was to explore the hypothesis that IL-19 mediates anti-inflammatory effects on vascular cells by inhibiting the expression of pro-inflammatory genes, such intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, IL-1β, IL-8, and monocyte chemotactic protein (MCP)-1, through modulation of the mRNA stability factor HuR by post- transcriptional (e.g., microRNA) and post-translational (e.g., serine phosphorylation) mechanisms. METHODS and RESULTS: We found that IL-19 can significantly inhibit tumor necrosis factor (TNF)-α-driven ICAM-1 and VCAM-1 mRNA and protein abundance in cultured human coronary artery ECs (p < 0.01). IL-19 treatment of ECs, but not monocytes, significantly inhibited monocyte adhesion to cultured EC monolayers (p < 0.01). In wild-type mice, systemic administration of IL-19 significantly reduced TNF-α-induced leukocyte rolling and adhesion as quantitated by intravital microscopy (p < 0.05). IL-19 failed to inhibit TNF-α-induced nuclear factor (NF)-κB activation in ECs. IL-19 inhibited nuclear-to-cytoplasmic translocation of HuR and significantly reduced mRNA stability of ICAM-1 and VCAM-1 (p < 0.01 ). IL-19 significantly inhibited serine-phosphorylation of HuR, which is required for its translocation, and significantly increased expression of the putative HuR regulator microRNA (miR)-133 in VSMCs. CONCLUSIONS: These data are the first to report that IL-19 can reduce leukocyte-EC interactions, and to propose reduction in HuR-mediated mRNA stability of ICAM-1 and VCAM-1 as a mechanism. We conclude that expression of IL-19 by ECs and VSMCs may represent an auto-regulatory mechanism to promote resolution of the vascular response to inflammation. These results suggest that IL-19 is anti-inflammatory in vascular cells and, therefore, may be of therapeutic value in atherosclerotic vascular disease. / Physiology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/1171 |
| Date | January 2015 |
| Creators | England, Ross N. |
| Contributors | Autieri, Michael V., Scalia, Rosario, Eguchi, Satoru, Rizzo, Victor, Litvin, Judith |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 110 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/1153, Theses and Dissertations |
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