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A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-ß1 in Steroid-Resistant Airway Diseases.
Li, Meina; Keenan, Christine R; Lopez-Campos, Guillermo; Mangum, Jonathan E; Chen, Qianyu; Prodanovic, Danica; Xia, Yuxiu C; Langenbach, Shenna Y; Harris, Trudi; Hofferek, Vinzenz; Reid, Gavin E; Stewart, Alastair G.
Afiliação
  • Li M; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Keenan CR; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Lopez-Campos G; Health and Biomedical Informatics Centre, Melbourne Medical School, University of Melbourne, Parkville, VIC 3010, Australia; Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7BL, UK.
  • Mangum JE; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Chen Q; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Prodanovic D; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Xia YC; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Langenbach SY; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Harris T; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia.
  • Hofferek V; Max Plank Institute of Molecular Plant Physiology, Potsdam, Germany; School of Chemistry, University of Melbourne, Parkville, VIC 3010, Australia.
  • Reid GE; School of Chemistry, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia; Bio21 Molecular Science and Biotechnology Institute. University of Melbourne, Parkville, VIC 3010, Australia.
  • Stewart AG; Department of Pharmacology & Therapeutics, School of Biomedical Science, University of Melbourne, Parkville, VIC 3010, Australia; ARC Centre for Personalised Therapeutics Technologies, Parkville, VIC, Australia. Electronic address: astew@unimelb.edu.au.
iScience ; 12: 232-246, 2019 Feb 22.
Article em En | MEDLINE | ID: mdl-30711747
Impaired therapeutic responses to anti-inflammatory glucocorticoids (GC) in chronic respiratory diseases are partly attributable to interleukins and transforming growth factor ß1 (TGF-ß1). However, previous efforts to prevent induction of GC insensitivity by targeting established canonical and non-canonical TGF-ß1 pathways have been unsuccessful. Here we elucidate a TGF-ß1 signaling pathway modulating GC activity that involves LIM domain kinase 2-mediated phosphorylation of cofilin1. Severe, steroid-resistant asthmatic airway epithelium showed increased levels of immunoreactive phospho-cofilin1. Phospho-cofilin1 was implicated in the activation of phospholipase D (PLD) to generate the effector(s) (lyso)phosphatidic acid, which mimics the TGF-ß1-induced GC insensitivity. TGF-ß1 induction of the nuclear hormone receptor corepressor, SMRT (NCOR2), was dependent on cofilin1 and PLD activities. Depletion of SMRT prevented GC insensitivity. This pathway for GC insensitivity offers several promising drug targets that potentially enable a safer approach to the modulation of TGF-ß1 in chronic inflammatory diseases than is afforded by global TGF-ß1 inhibition.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: IScience Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: IScience Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Austrália