The development of multiple vascular diseases is inflammatory in nature. Little is known about the potential direct protective effects of anti-inflammatory cytokines on vascular smooth muscle cell (VSMC) pathophysiology, lnterleukin-19 (IL-19) is a member of the IL-10 family of anti-inflammatory cytokines. Our group was the first to report on the expression of IL-19 in vascular cells. We have found that IL-19 is not expressed in quiescent VSMC or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury. IL-19 is anti-proliferative for cultured, human coronary artery VSMC, and adenoviral delivery of IL-19 reduces intimal hyperplasia in angioplasty injured rat carotid arteries. IL-19 inhibits inflammation-stimulated expression of proliferative and inflammatory gene proteins. IL-19 transiently reduces expression of HuR, an inflammatory and proliferative gene mRNA stabilizing protein. IL-19 inhibits serine phosphorylation of HuR, which is necessary for its cytoplasmic translocation and function, indicating that not only does IL-19 decrease HuR accumulation, but also its activity. Actinomycin D blockade of transcription shows that IL-19 treatment reduced abundance of these inflammatory and proliferative mRNAs to 50-60% of untreated controls. (P<0.001 for all genes). HuR overexpression by transfection of HuR cDNA increased COX-2 mRNA abundance, while HuR siRNA decreased COX-2 mRNA abundance. Together, these data indicate that one potential mechanism whereby IL-19 inhibits VSMC proliferation and gene expression is by a reduction in expression and function of HuR. Our working hypothesis is that expression of the immunomodulatory cytokine IL-19 by activated VSMC may represent a negative auto-regulatory feedback mechanism to promote resolution of the vascular response to injury, and at least one mechanism is by modulation of HuR expression and function.
AIM 1 We will determine the mechanism whereby IL-19 down regulates HuR expression and function. We will determine how IL-19 effects HuR mRNA stability, protein degradation and signaling pathways involved in HuR phosphorylation, and correlate these with translocation.
AIM 2 We will determine if modulation of HuR expression mimics IL-19 treatment of VSMC.
This aim will determine if HuR is the primary effector of IL-19's effects on VSMC.

Public Health Relevance

Many vascular diseases are inflammatory in nature. Little is known about the direct protective effects of anti-inflammatory cytokines in the prevention of vascular diseases. IL-19 is an anti- inflammatory cytokine that as the potential to ameliorate some vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL095329-02
Application #
8011068
Study Section
Special Emphasis Panel (ZRG1-F10-S (21))
Program Officer
Meadows, Tawanna
Project Start
2009-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2011
Total Cost
$46,800
Indirect Cost
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Cuneo, Anthony A; Herrick, David; Autieri, Michael V (2010) Il-19 reduces VSMC activation by regulation of mRNA regulatory factor HuR and reduction of mRNA stability. J Mol Cell Cardiol 49:647-54