IL‐19 reduces VSMC activation by regulation of mRNA binding proteins and reduction of inflammatory gene expression

Abstract

Many vascular diseases are inflammatory in nature. Interleukin‐19 (IL‐19) is a recently described Th2, anti‐inflammatory cytokine. We have previously reported that IL‐19 is induced in VSMC by inflammatory cytokines and in arteries by injury. IL‐19 is anti‐proliferative and anti‐restenotic for VSMC. The purpose of this study is to determine the mechanism of these effects. IL‐19 reduces inflammation‐stimulated expression of proliferative and inflammatory gene proteins, including Cyclins B and D, CDK, IL‐8, and COX2. Importantly, IL‐19 transiently reduces expression of HuR protein and mRNA, a stabilizing inflammatory gene mRNA binding protein. Actinomycin D transcription blockade demonstrated that IL‐19 treatment reduced abundance of these mRNAs to 50‐60% of untreated controls. (P<0.001 for all). The mRNA stabilizing function of HuR is linked to its phosphorylation and cytoplasmic translocation. IL‐19 reduces HuR cytoplasmic translocation, PKCa activation, and subsequent phosphorylation of HuR. Together, these data indicate that one potential mechanism whereby IL‐19 inhibits VSMC activation is by a reduction in HuR expression and function.