title: Receptor-selective IL-4 mutein modulates inflammatory vascular cell phenotypes and attenuates atherogenesis in apolipoprotein E-knockout mice.
abstract: 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.
authors.affiliation: Department of Health Management, The Third Xiangya Hospital, Central South University, Hunan, China; Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. Electronic address: linyanhui1979@hotmail.com.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Health Management, The Third Xiangya Hospital, Central South University, Hunan, China.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: Apo-E knockout mouse; Atherogenesis; Endothelial cells; IL-4; Macrophages; Vascular smooth muscle cells