A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases.

Meina Li, Christine R Keenan, Guillermo Lopez Campos, Jonathan E. Mangum, Qianyu Chen, Danica Prodanovic, Yuxiu C. Xia, Sheena Y. Langenbach, Trudi Harris, Vinzenz Hofferek, Gavin E. Reid, Alastair G Stewart

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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.
Original languageEnglish
Pages (from-to)232-246
JournaliScience
Volume12
Early online date21 Jan 2019
DOIs
Publication statusPublished - 22 Feb 2019

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Transforming Growth Factors
Glucocorticoids
Steroids
Phospholipase D
Lim Kinases
Chronic Disease
Co-Repressor Proteins
Phosphatidic Acids
Interleukins
Cytoplasmic and Nuclear Receptors
Anti-Inflammatory Agents
Epithelium
Phosphorylation
Pharmaceutical Preparations

Keywords

  • Biochemistry
  • Biological Sciences
  • Cell Biology
  • Molecular Biology

Cite this

Li, Meina ; Keenan, Christine R ; Lopez Campos, Guillermo ; Mangum, Jonathan E. ; Chen, Qianyu ; Prodanovic, Danica ; Xia, Yuxiu C. ; Langenbach, Sheena Y. ; Harris, Trudi ; Hofferek, Vinzenz ; Reid, Gavin E. ; Stewart, Alastair G. / A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases. In: iScience. 2019 ; Vol. 12. pp. 232-246.
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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.",
keywords = "Biochemistry, Biological Sciences, Cell Biology, Molecular Biology",
author = "Meina Li and Keenan, {Christine R} and {Lopez Campos}, Guillermo and Mangum, {Jonathan E.} and Qianyu Chen and Danica Prodanovic and Xia, {Yuxiu C.} and Langenbach, {Sheena Y.} and Trudi Harris and Vinzenz Hofferek and Reid, {Gavin E.} and Stewart, {Alastair G}",
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Li, M, Keenan, CR, Lopez Campos, G, Mangum, JE, Chen, Q, Prodanovic, D, Xia, YC, Langenbach, SY, Harris, T, Hofferek, V, Reid, GE & Stewart, AG 2019, 'A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases.', iScience, vol. 12, pp. 232-246. https://doi.org/10.1016/j.isci.2019.01.023

A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases. / Li, Meina; Keenan, Christine R; Lopez Campos, Guillermo; Mangum, Jonathan E. ; Chen, Qianyu; Prodanovic, Danica; Xia, Yuxiu C. ; Langenbach, Sheena Y. ; Harris, Trudi; Hofferek, Vinzenz; Reid, Gavin E. ; Stewart, Alastair G.

In: iScience, Vol. 12, 22.02.2019, p. 232-246.

Research output: Contribution to journalArticle

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T1 - A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases.

AU - Li, Meina

AU - Keenan, Christine R

AU - Lopez Campos, Guillermo

AU - Mangum, Jonathan E.

AU - Chen, Qianyu

AU - Prodanovic, Danica

AU - Xia, Yuxiu C.

AU - Langenbach, Sheena Y.

AU - Harris, Trudi

AU - Hofferek, Vinzenz

AU - Reid, Gavin E.

AU - Stewart, Alastair G

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N2 - 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.

AB - 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.

KW - Biochemistry

KW - Biological Sciences

KW - Cell Biology

KW - Molecular Biology

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SP - 232

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JO - iScience

JF - iScience

SN - 2589-0042

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