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

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d235820e171">Objective</h5> <p id="P1">To test the hypothesis that loss of IL-19 exacerbates atherosclerosis.</p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d235820e176">Approach and Results</h5> <p id="P2"> <i>Il19</i> ^−/− mice were crossed into <i>Ldlr</i> ^−/− mice. Double knockout (dKO) mice had increased plaque burden in aortic arch and root compared to <i>Ldlr</i> ^−/− controls after 14 weeks of high fat diet (HFD). dKO mice injected with 10ng/g/day rmIL-19 had significantly less plaque compared to controls. qRT-PCR and western blot analysis revealed dKO mice had increased systemic and intraplaque polarization of T cells and macrophages to pro-inflammatory T _h1 and M1 phenotypes, and also significantly increased TNFα expression in spleen and aortic arch compared to <i>Ldlr</i> ^−/− controls. Bone marrow transplantantion suggests that immune cells participate in IL-19 protection. Bone marrow derived macrophages (BMDM) and vascular smooth muscle cells (VSMC) isolated from dKO mice had significantly greater expression of inflammatory cytokine mRNA and protein compared to controls. Spleen and aortic arch from dKO mice had significantly increased expression of the mRNA stability protein Human antigen R (HuR). BMDM and VSMC isolated from dKO mice also had greater HuR abundance. HuR stabilizes pro-inflammatory transcripts by binding AU-rich elements (AREs) in the 3′ untranslated region (UTR). Cytokine and HuR mRNA stability was increased in dKO BMDM and VSMC, which was rescued by addition of IL-19 to these cells. IL-19 induced expresson of miR133a, which targets and reduced HuR abundance; miR133a levels were lower in dKO mice compared to controls. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d235820e209">Conclusions</h5> <p id="P3">These data indicate that IL-19 is an atheroprotective cytokine which decreases abundance of HuR, leading to reduced inflammatory mRNA stability. </p> </div>