Receptor-selective IL-4 mutein modulates inflammatory vascular cell phenotypes and attenuates atherogenesis in apolipoprotein E-knockout mice

The therapeutic potential of interleukin-4-mediated immunomodulation has not been proven in atherogenesis. Type I IL-4 receptor consists of IL-4Rα and a common γ chain, whereas type II IL-4R is a heterodimer of IL-4Rα and IL-13Rα1. Reportedly, the human IL-4 mutein IL-4/R121E is able to act as an IL-4RI-specific agonist. Here, we investigated the effect of receptor-specific IL-4 mutein on vascular cell phenotypes and atherogenesis. Initially, a plasmid expressing murine IL-4/Q116E, analogous to human IL-4/R121E, was transfected to vascular lineage cells in-vitro. IL-4/Q116E induced the activation of STAT6 in b.End3 endothelial cells, Mm1 macrophages, and splenocytes isolated from C57BL6/J (B6) mice, but it failed to activate STAT6 in SMC and J774.1 macrophages. IL-4/Q116E induced the expression of vascular cell adhesion protein-1 in b.End3 cells but not in SMC. IL-4/Q116E did not exhibit pro-inflammatory actions in either macrophage cell line. Splenocytes were also infected with an adenovirus vector expressing IL-4/Q116E (AdIL-4/Q116E). Enzyme-linked immunosorbent assay for interferon-γ, IL-10 and IL-13 revealed that AdIL-4/Q116E-infected splenocytes showed Th2 deviation. Th2 deviation and M2 marker up-regulation were further revealed in ex-vivo assays using the splenocytes isolated from AdIL-4/Q116E-infected apolipoprotein-E knockout (ApoEKO) mice. Finally, adenoviral induction of IL-4/Q116E, but not wild type IL-4, double mutein IL-4/Q116D/Y119D or control β-galactosidase, significantly attenuated in-vivo atherogenesis of ApoEKO mice. Our data suggest that IL-4 signaling plays a pivotal role in the regulation of vascular cell phenotypes, and atherogenesis. The IL-4RI-selective mutein IL-4/Q116E may have therapeutic potential in vascular diseases.