IL‐19 decreases ox‐LDL induced VSMC activation by suppression of scavenger receptor expression and reduction of ox‐LDL uptake

Abstract

Atherosclerosis is inflammatory in nature and oxidized low density lipoprotein (ox‐LDL) has activating effects on vascular smooth muscle cells (VSMC). Interleukin‐19 (IL‐19) is a recently described Th2 anti‐inflammatory cytokine. We have previously reported that IL‐19 expression is induced in VSMC by inflammatory cytokines and in arteries by injury. Our hypothesis is that IL‐19 participates in a negative autocrine regulatory feedback mechanism to ameliorate inflammation. The purpose of this study is to determine the molecular mechanism(s) of IL‐19's anti‐inflammatory role in atherosclerosis. IL‐19 decreases the abundance of ox‐LDL induced COX‐2 protein expression. Fluorescently labeled ox‐LDL uptake is inhibited by IL‐19, as determined by flow cytometry and immunocytochemistry. IL‐19 reduces the abundance of LOX‐1 and CX‐CL16 mRNA, VSMC receptors which internalize ox‐LDL. Each of these receptors have AU‐rich elements (ARE) in their 3' UTR which act as binding sites for the RNA‐binding protein HuR, an inflammatory mRNA stabilizing protein. The mRNA stabilizing function of HuR is linked to its cytoplasmic translocation. IL‐19 inhibits HuR protein abundance and ox‐LDL induced HuR cytoplasmic translocation. Together, these data indicate that at least one of IL‐19's anti‐atherosclerotic mechanisms in VSMC involves reduction of ox‐LDL uptake, primarily through reduced scavenger receptor abundance.Work supported by grant HL063810 and HL090885 from NHLBI, and grant 0455562U from AHA, to M.V.A.. A.A.C. received NHLBI Ruth L. Kirchstein Predoctoral fellowship F30HL095329.