PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis

Transforming growth factor beta (TGFβ) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFβ signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxis...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2011-01, Vol.6 (1), p.e15909-e15909
Main Authors: Kulkarni, Ajit A, Thatcher, Thomas H, Olsen, Keith C, Maggirwar, Sanjay B, Phipps, Richard P, Sime, Patricia J
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Actin
AKT protein
Apoptosis
Biology
Calponin
Cardiomyocytes
Cell Differentiation - drug effects
Critical care
Cytokines
Dentistry
Diabetes
Differentiation
Environmental health
Extracellular matrix
Fibroblasts
Fibrosis
Fibrosis - drug therapy
Growth factors
Humans
Hypoxia
Immunology
Inhibition
Kinases
Ligands
Lung diseases
MAP kinase
Medicine
Pathogenesis
Peroxisome proliferator-activated receptors
Phosphatase
Phosphatidylinositol 3-Kinase - metabolism
Phosphorylation
Phosphorylation - drug effects
Post-transcription
Post-translation
PPAR gamma - metabolism
Proteins
Proto-Oncogene Proteins c-akt - metabolism
PTEN protein
Pulmonary fibrosis
Rodents
Scleroderma
Signal transduction
Signal Transduction - drug effects
Signaling
Smad protein
Smooth muscle
Transcription factors
Transforming Growth Factor beta - pharmacology
Transforming growth factor-b
Western blotting
Wound healing
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Transforming growth factor beta (TGFβ) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFβ signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands inhibit TGFβ-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. TGFβ also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway leading to phosphorylation of Akt(S473). Here, we report that PPAR-γ ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15d-prostaglandin J(2) (15d-PGJ(2)), inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF) fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR-γ-independent mechanism. The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFβ-stimulated myofibroblast differentiation, as determined by Western blotting for α-smooth muscle actin and calponin. Prostaglandin A(1) (PGA(1)), a structural analogue of 15d-PGJ(2) with an electrophilic center, also reduced TGFβ-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2) and CDDO is dependent on their electrophilic properties. PPAR-γ ligands inhibited TGFβ-induced Akt phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFβ-induced phosphorylation of FAK, a kinase that acts upstream of Akt. Thus, PPAR-γ ligands inhibit TGFβ signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of PPAR-γ ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0015909