Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis
Gang Liu, Marion A. Cooley, Andrew G. Jarnicki, Theo Borghuis, Prema M. Nair, Gavin Tjin, Alan C. Hsu, Tatt Jhong Haw, Michael Fricker, Celeste L. Harrison, Bernadette Jones, Nicole G. Hansbro, Peter A. Wark, Jay C. Horvat, W. Scott Argraves, Brian G. Oliver, Darryl A. Knight, Janette K. Burgess, Philip M. Hansbro
Gang Liu, Marion A. Cooley, Andrew G. Jarnicki, Theo Borghuis, Prema M. Nair, Gavin Tjin, Alan C. Hsu, Tatt Jhong Haw, Michael Fricker, Celeste L. Harrison, Bernadette Jones, Nicole G. Hansbro, Peter A. Wark, Jay C. Horvat, W. Scott Argraves, Brian G. Oliver, Darryl A. Knight, Janette K. Burgess, Philip M. Hansbro
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Research Article Cell biology Immunology

Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

Abstract

Tissue remodeling/fibrosis is a major feature of all fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). It is underpinned by accumulating extracellular matrix (ECM) proteins. Fibulin-1c (Fbln1c) is a matricellular ECM protein associated with lung fibrosis in both humans and mice and stabilizes collagen formation. Here we discovered that Fbln1c was increased in the lung tissues of patients with IPF and experimental bleomycin-induced pulmonary fibrosis. Fbln1c-deficient (Fbln1c–/–) mice had reduced pulmonary remodeling/fibrosis and improved lung function after bleomycin challenge. Fbln1c interacted with fibronectin, periostin, and tenascin-C in collagen deposits following bleomycin challenge. In a potentially novel mechanism of fibrosis, Fbln1c bound to latent TGF-β–binding protein 1 (LTBP1) to induce TGF-β activation and mediated downstream Smad3 phosphorylation/signaling. This process increased myofibroblast numbers and collagen deposition. Fbln1c and LTBP1 colocalized in lung tissues from patients with IPF. Thus, Fbln1c may be a novel driver of TGF-β–induced fibrosis involving LTBP1 and may be an upstream therapeutic target.

Authors

Gang Liu, Marion A. Cooley, Andrew G. Jarnicki, Theo Borghuis, Prema M. Nair, Gavin Tjin, Alan C. Hsu, Tatt Jhong Haw, Michael Fricker, Celeste L. Harrison, Bernadette Jones, Nicole G. Hansbro, Peter A. Wark, Jay C. Horvat, W. Scott Argraves, Brian G. Oliver, Darryl A. Knight, Janette K. Burgess, Philip M. Hansbro

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Figure 4

Fbln1c binds with LTBP1 to induce TGF-β activation.

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Fbln1c binds with LTBP1 to induce TGF-β activation. A single bleomycin c...
A single bleomycin challenge was used to induce pulmonary fibrosis in WT and Fbln1c–/– mice that were assessed 28 days later. Controls received PBS. TGF-β (A) mRNA and (B) active protein levels in whole lung tissues measured using qRT-PCR and ELISA (n = 4–8). (C) LTBP1 levels in lungs measured using immunoblot (left) and fold change quantification using densitometry with normalization to β-actin (right, n = 5–8). (D) p-Smad3 protein levels in lungs measured using immunoblot (left) and fold change quantified using densitometry with normalization to vinculin (right, n = 5–8). (E) Immunoprecipitation (IP) of Fbln1c protein from whole lung tissues and detection of Fbln1c and LTBP1 binding using immunoblot (IB). IB analysis of lung tissues before (input) and after IP. Statistical differences were determined with 1-way ANOVA followed by Bonferroni’s posttest. *P < 0.05, and **P < 0.01 compared with PBS-challenged WT controls. †P < 0.05 compared with bleomycin-challenged WT controls.