title: Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization.
abstract: Accumulating evidence supports the importance of macrophage plasticity in a broad spectrum of biological processes operative in health and disease. A major locus of control regulating macrophage polarization is at the transcriptional level, and several major pathways have been elucidated in recent years. In this study, we identify the Kruppel-like transcription factor 6 (KLF6) as a molecular toggle controlling macrophage speciation. KLF6 expression was robustly induced by pro-inflammatory M1 stimuli (e.g. LPS and IFN-γ) and strongly suppressed by M2 stimuli (e.g. IL4 and IL-13) in human and murine macrophages. Gain- and loss-of-function studies suggest that KLF6 is required for optimal LPS-induced pro-inflammatory gene expression, acting cooperatively with NF-κB. Furthermore, KLF6 inhibits anti-inflammatory gene expression by negatively regulating peroxisome proliferator-activated receptor γ expression in macrophages. Collectively, these observations identify KLF6 as a novel transcriptional regulator of macrophage polarization.
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine Cleveland, Ohio 44106.
authors.forename: Dipali
authors.initials: D
authors.lastname: Date
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106.
authors.forename: Riku
authors.initials: R
authors.lastname: Das
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine Cleveland, Ohio 44106.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine Cleveland, Ohio 44106.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine Cleveland, Ohio 44106.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine Cleveland, Ohio 44106. Electronic address: ghm4@case.edu.
authors.forename: Ganapati H
authors.initials: GH
authors.lastname: Mahabeleshwar
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: C105465:KLF6 protein, human; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins
keywords: Cellular Immune Response; Gene Regulation; Inflammation; Kruppel-like Transcription Factor 6; Macrophages; Transcription Regulation