In:
The Journal of Pathology, Wiley, Vol. 232, No. 4 ( 2014-03), p. 458-472
Abstract:
Idiopathic pulmonary fibrosis ( IPF ) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix ( ECM ) in the lungs. TGF‐ β 1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. α B‐crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of α B‐crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad‐dependent pathway. We demonstrate here that α B‐crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that α B‐crystallin‐deficient mice are protected from bleomycin‐induced fibrosis. Similar protection from fibrosis was observed in α B‐crystallin KO mice after transient adenoviral‐mediated over‐expression of IL‐1 β or TGF‐ β 1. We show in vitro in primary epithelial cells and fibroblasts that α B‐crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF‐ β 1–Smad pathway and the consequent activation of TGF‐ β 1 downstream genes. α B‐crystallin over‐expression disrupts Smad4 mono‐ubiquitination by interacting with its E3–ubiquitin ligase, TIF1 γ , thus limiting its nuclear export. Conversely, in the absence of α B‐crystallin, TIF1 γ can freely interact with Smad4. Consequently, Smad4 mono‐ubiquitination and nuclear export are favoured and thus TGF‐ β 1–Smad4 pro‐fibrotic activity is inhibited. This study demonstrates that α B‐crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Type of Medium:
Online Resource
ISSN:
0022-3417
,
1096-9896
DOI:
10.1002/path.2014.232.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
1475280-3
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