A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-beta 1 in Steroid-Resistant Airway Diseases

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    Author
    Li, M; Keenan, CR; Lopez-Campos, G; Mangum, JE; Chen, Q; Prodanovic, D; Xia, YC; Langenbach, SY; Harris, T; Hofferek, V; ...
    Date
    2019-02-22
    Source Title
    iScience
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Langenbach, Shenna; Stewart, Alastair; Xia, Yuxiu; Mangum, Jonathan; Lopez Campos, Guillermo; Reid, Gavin; Hofferek, Vinzenz; Li, Meina; Keenan, Christine; Chen, Qianyu; ...
    Affiliation
    Pharmacology and Therapeutics
    School of Chemistry

    Biochemistry and Molecular Biology
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    Document Type
    Journal Article
    Citations
    Li, M., Keenan, C. R., Lopez-Campos, G., Mangum, J. E., Chen, Q., Prodanovic, D., Xia, Y. C., Langenbach, S. Y., Harris, T., Hofferek, V., Reid, G. E. & Stewart, A. G. (2019). A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-beta 1 in Steroid-Resistant Airway Diseases. ISCIENCE, 12, pp.232-+. https://doi.org/10.1016/j.isci.2019.01.023.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253784
    DOI
    10.1016/j.isci.2019.01.023
    Abstract
    Impaired therapeutic responses to anti-inflammatory glucocorticoids (GC) in chronic respiratory diseases are partly attributable to interleukins and transforming growth factor β1 (TGF-β1). However, previous efforts to prevent induction of GC insensitivity by targeting established canonical and non-canonical TGF-β1 pathways have been unsuccessful. Here we elucidate a TGF-β1 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-β1-induced GC insensitivity. TGF-β1 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-β1 in chronic inflammatory diseases than is afforded by global TGF-β1 inhibition.

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