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.
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.
|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|