Journal article

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

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

ISCIENCE | CELL PRESS | Published : 2019

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 effect..

View full abstract

Grants

Awarded by NHMRC


Funding Acknowledgements

We thank the expert assistance from the Center for Translational Pathology, The University of Melbourne, for RNA-seq in this study, and Mass Spectrometry and Proteomics Platform, Bio21 Institute's Research Facility, The University of Melbourne, for proteomic analysis in this study. We also acknowledge Associate Professor Vera Ignjatovic for assistance in analyzing proteomic results. We thank the research and clinical investigators of the MESCA group, including C.F. Robertson (Royal Children's Hospital Melbourne), J. Wilson (Monash University), D. Smallwood, E. Horak, and M. Roberts (Royal Children's Hospital Melbourne). This work was funded by grants from Asthma Australia; NHMRC (1059665, 1137171) and Victorian Medical Research Acceleration Fund.