iScience
Volume 12, 22 February 2019, Pages 232-246
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Article
A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases

https://doi.org/10.1016/j.isci.2019.01.023Get rights and content
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Highlights

  • TGF-β1 extensively impairs GC activity

  • Phospho-cofilin1 is a key link in TGF-β1 signaling cascade subserving GC insensitivity

  • Phospho-cofilin1-activated phospholipase D (PLD) reduces GC activity

  • SMRT induction downstream of PLD mediates TGF-β1 impairment of GC activity

Summary

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.

Subject Areas

Biological Sciences
Biochemistry
Molecular Biology
Cell Biology

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