title: Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis.
abstract: M2 macrophages are implicated in the development of pulmonary fibrosis as they generate profibrotic signals. The polarization process, at least in part, is regulated by epigenetic modulation. Because Cu,Zn-superoxide dismutase-induced H2O2 can polarize macrophages to a profibrotic M2 phenotype, we hypothesized that modulation of the redox state of the cell is involved in the epigenetic modulation of the macrophage phenotype. In this study, we show that signal transducer and activator of transcription 6 (STAT6) regulates Jumonji domain containing (Jmjd) 3, a histone H3 lysine 27 demethylase, and mutation of a redox-sensitive cysteine in STAT6 attenuates jmjd3 expression. Moreover, Jmjd3 deficiency abrogates profibrotic M2 gene expression. Treatment with leflunomide, which reduces mitochondrial reactive oxygen species production and tyrosine phosphorylation, inhibits jmjd3 expression and M2 polarization, as well as development of a fibrotic phenotype. Taken together, these observations provide evidence that the redox regulation of Jmjd3 is a unique regulatory mechanism for Cu,Zn-superoxide dismutase-mediated profibrotic M2 polarization. Furthermore, leflunomide, which reduces reactive oxygen species production and tyrosine phosphorylation, may prove to be therapeutic in the treatment of asbestos-induced pulmonary fibrosis.
authors.affiliation: Departments of 1Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.affiliation: Departments of 1Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology.|2 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larson-Casey
authors.affiliation: 2 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Linlin
authors.initials: L
authors.lastname: Gu
authors.affiliation: 3 Internal Medicine, Carver College of Medicine, and.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: 3 Internal Medicine, Carver College of Medicine, and.
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Departments of 1Radiation Oncology and the Graduate Program in Free Radical and Radiation Biology.|4 Human Toxicology, College of Public Health, University of Iowa, Iowa City, Iowa.|5 Iowa City Veterans Administration Center, Iowa City, Iowa.|2 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.|6 Birmingham Veterans Administration Center, Birmingham, Alabama.
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000818:Animals; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D000077339:Leflunomide; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism*
chemical_list: D007555:Isoxazoles; D017382:Reactive Oxygen Species; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D056484:Jumonji Domain-Containing Histone Demethylases; D000072105:Superoxide Dismutase-1; C523761:Kdm6b protein, mouse; D000077339:Leflunomide
keywords: Cu,Zn–superoxide dismutase; Jumonji domain containing 3; alternative activation; macrophage; pulmonary fibrosis