The overall goals of this application are to demonstrate that Interleukin-19 (IL-19), a Th2 anti- inflammatory interleukin, can attenuate atherosclerosis, and identify the potential mechanisms of this inhibition. IL-19 is a newly described Th2, (T regulatory) anti-inflammatory interleukin which until our work, had been ascribed to be inflammatory cell-specific. We remain the only laboratory to investigate a role for this interleukin in vascular biology, particularly with respect to EC and VSMC pathophysiology, and to demonstrate molecular mechanisms for these effects. We previously reported that;1- IL-19 is not detectible in normal artery, but is induced in EC and VSMC in human atherosclerotic lesions;2- addition of IL-19 to VSMC reduces their migration, proliferation, and abundance of proliferative and inflammatory proteins;3- IL-19 does NOT inhibit NF-kB, but does reduce the stability of inflammatory and proliferative mRNA transcripts in an HuR-dependent manner;4- IL-19 induces expression of the vascular and cyto-protective protein Hemeoxygenase-1 (HO-1), and reduces apoptosis induced by vascular reactive oxygen species (ROS) in an HO-1 dependent manner. In this application we present preliminary data showing that addition of recombinant IL-19 to LDLR-/- mice fed an atherogenic diet significantly and dramatically decreases atherosclerotic plaque, and IL-19-/- mice have an exacerbated response to ligation injury. Based on published and preliminary data, we hypothesize that there are multiple, pleiotropic mechanisms for these protective effects, and Specific Aims are designed to test each of these mechanisms.
In Aim 1, we will determine if absence of IL-19 exacerbates, and if over expression attenuates atherosclerosis.
Aim 2 will test the hypothesis that one mechanism of IL-19 protection is primarily facilitated by adoptive immune system polarization to Th2.
Aim 3 will test the hypothesis that IL-19 atheroprotection is mediated by reduction in leukocyte-endothelial cell interaction, and/or IL-19 induction of HO-1 expression.
Aim 4 will determine the molecular mechanisms of how IL- 19 decreases inflammatory gene abundance. This application is potentially paradigm-changing as it will implicate a Th2 interleukin as an endogenous cytokine expressed by inflamed vascular cells with multiple autocrine and paracrine dampening effects. It will identify novel molecular mechanisms and targets of anti-inflammatory pathways in these cells.

Public Health Relevance

Atherosclerotic vascular disease continues to account for 50% of all mortality in the United States. Interleukin-19 (IL-19) is a newly described anti-inflammatory interleukin expressed in injured arteries. The overall goal of this application is to test the hypothesis that IL-19 can be protective and inhibit atherosclerosis and determine the mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL117724-01A1
Application #
8594550
Study Section
Special Emphasis Panel (ZRG1-VH-D (03))
Program Officer
Kirby, Ruth
Project Start
2013-07-23
Project End
2017-06-30
Budget Start
2013-07-23
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$401,089
Indirect Cost
$142,322
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Richards, James; Gabunia, Khatuna; Kelemen, Sheri E et al. (2015) Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization. J Mol Cell Cardiol 79:21-31
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Hemmasizadeh, Ali; Autieri, Michael; Darvish, Kurosh (2012) Multilayer material properties of aorta determined from nanoindentation tests. J Mech Behav Biomed Mater 15:199-207