Genetic Deletion of IL (Interleukin)-19 Exacerbates Atherogenesis in Il19−−×Ldlr−− Double Knockout Mice by Dysregulation of mRNA Stability Protein HuR (Human antigen R).pdf

Objective—To test the hypothesis that loss of IL (interleukin)-19 exacerbates atherosclerosis.<br>Approach and Results—Il19−/− mice were crossed into Ldlr−/− (low-density lipoprotein receptor knock out) mice. Double<br>knockout (dKO) mice had increased plaque burden in aortic arch and root compared with Ldlr−/− controls after 14 weeks<br>of high-fat diet (HFD). dKO mice injected with 10 ng/g per day rmIL-19 had significantly less plaque compared with<br>controls. qRT-PCR and Western blot analysis revealed dKO mice had increased systemic and intraplaque polarization of T<br>cells and macrophages to proinflammatory Th1 and M1 phenotypes, and also significantly increased TNF (tumor necrosis<br>factor)-α expression in spleen and aortic arch compared with Ldlr−/− controls. Bone marrow transplantation suggests<br>that immune cells participate in IL-19 protection. Bone marrow-derived macrophages and vascular smooth muscle cells<br>isolated from dKO mice had a significantly greater expression of inflammatory cytokine mRNA and protein compared<br>with controls. Spleen and aortic arch from dKO mice had significantly increased expression of the mRNA stability<br>protein HuR (human antigen R). Bone marrow-derived macrophage and vascular smooth muscle cell isolated from dKO<br>mice also had greater HuR abundance. HuR stabilizes proinflammatory transcripts by binding AU-rich elements in the<br>3′ untranslated region. Cytokine and HuR mRNA stability were increased in dKO bone marrow-derived macrophage<br>and vascular smooth muscle cell, which was rescued by addition of IL-19 to these cells. IL-19–induced expression of<br>miR133a, which targets and reduced HuR abundance; miR133a levels were lower in dKO mice compared with controls.<br>Conclusions—These data indicate that IL-19 is an atheroprotective cytokine which decreases the abundance of HuR,<br>leading to reduced inflammatory mRNA stability.