title: Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop.
abstract: Using forward and reverse genetics and global gene expression analyses, we explored the crosstalk between the IκB kinase β (IKKβ) and the transforming growth factor β (TGFβ) signaling pathways. We show that in vitro ablation of Ikkβ in fibroblasts led to progressive ROS accumulation and TGFβ activation, and ultimately accelerated cell migration, fibroblast-myofibroblast transformation and senescence. Mechanistically, the basal IKKβ activity was required for anti-oxidant gene expression and redox homeostasis. Lacking this activity, IKKβ-null cells showed ROS accumulation and activation of stress-sensitive transcription factor AP-1/c-Jun. AP-1/c-Jun activation led to up-regulation of the Tgfβ2 promoter, which in turn further potentiated intracellular ROS through the induction of NADPH oxidase (NOX). These data suggest that by blocking the autocrine amplification of a ROS-TGFβ loop IKKβ plays a crucial role in the prevention of fibroblast-myofibroblast transformation and senescence.
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mongan
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Jingcai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Sartor
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Niu
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Kao
authors.affiliation: Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA. ying.xia@uc.edu.|Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA. ying.xia@uc.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D016922:Cellular Senescence; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000099156:Superoxide Dismutase 2
keywords: IkB kinase β (IKKβ); myofibroblast; nuclear factor κB (NF-κB); reactive oxygen species (ROS); senescence; transforming growth factors β (TGFβ)