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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop.

Authors: Chen, Liang; Peng, Zhimin; Meng, Qinghang; Mongan, Maureen; Wang, Jingcai; Sartor, Maureen; Chen, Jing; Niu, Liang; Medvedovic, Mario; Kao, Winston; Xia, Ying

Published In Protein Cell, (2016 May)

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.

PubMed ID: 26946493 Exiting the NIEHS site

MeSH Terms: Adenoviridae/genetics; Animals; Autocrine Communication/physiology*; Cell Line; Cell Movement; Cellular Senescence*; Genetic Vectors/genetics; Genetic Vectors/metabolism; I-kappa B Kinase/deficiency; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism*; JNK Mitogen-Activated Protein Kinases/metabolism; Mice; Myofibroblasts/cytology; Myofibroblasts/metabolism; NADPH Oxidases/metabolism; Oxidative Stress; Promoter Regions, Genetic; Reactive Oxygen Species/metabolism*; Signal Transduction; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Transcription Factor AP-1/metabolism; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism*; Up-Regulation

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Last Reviewed: October 02, 2024