The IL-6 Trans-Signaling-STAT3 Pathway Mediates ECM and Cellular Proliferation in Fibroblasts from Hypertrophic Scar

Ray, Sutapa; Ju, Xiaoxi; Sun, Hongying; Finnerty, Celeste C.; Herndon, David N.; Brasier, Allan R.

doi:10.1038/jid.2012.499

Cited by 99 publications

(84 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The involvement of STAT3, AKT, and Wnt/b-catenin pathways has already been reported in skin fibrosis (19, 34, 35) but the consequences of their coinhibition remain to be assessed. On one hand, STAT3 triggers a transduction signal that is required for the synthesis of the extracellular matrix and cellular proliferation of fibroblasts isolated from hypertrophic scars (36). In keloids, a fibrotic disease, STAT3 promotes collagen synthesis, proliferation, and migration of fibroblasts (37,38).…”

Section: Discussionmentioning

confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Curiously, the protooncogene MYCN, which is dysregulated in diverse cancers, was highly upregulated in MMP-19-deficient fibroblasts. Upregulation of this gene has been noticed in the exaggerated fibroblast proliferation associated with hypertrophic scar formation (17). The upregulation of this gene may be related to the increase of SET and MYND domain-containing protein 3, a histone methyltransferase that may activate the transcription of a set of downstream genes, including MYCN, and that also induces cell migration and proliferation (18).…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype

Jara

Calyeca

Romero

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/ myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient (Mmp19Ϫ/Ϫ) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19Ϫ/Ϫ lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19Ϫ/Ϫ lung fibroblasts showed increased ␣1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-␤ treatment and increased smooth muscle-␣ actin expression (P Ͻ 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation (P Ͻ 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel (P Ͻ 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation. lung fibrosis; matrix metalloproteinase; fibroblasts; collagen IDIOPATHIC PULMONARY FIBROSIS (IPF) is a progressive and usually lethal lung disease of unknown etiology and without current effective therapy (15). It is characterized by injury and aberrant activation of the alveolar epithelium, which induces, through the release of a variety of growth factors, cytokines, and matrix metalloproteinases (MMPs), a flow of dysregulated epithelial-fibroblast crosstalk (20). Activated epithelial cells provoke the migration, proliferation, and activation of mesenchymal cells, with the formation of fibroblast and myofibroblast foci, whereas activated myofibroblasts secrete exaggerated amounts of extracellular matrix (ECM) molecules culminating in the destruction of the lung parenchyma (5). However, the molecular mechanisms involved in IPF development and progression are uncertain. Studies in our group and others have shown that some MMPs such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in IPF, playing diverse roles in the fibrotic response; however, the exact mechanisms are not well characterized (4,10,11,21,24,27). Recently, we identified the overexpression of MMP-19 in the hyperplastic alveolar epithelium of IPF lungs and demonstrated that, surprisingly, mice lacking this MMP developed an exacerbated bleomycin-induced lung fibrosis (25). Perturbations of MMP-19 levels in epithelial cells in vivo and in vitro were associated with changes...

show abstract

“…The total cell numbers were counted, and cell viability was determined by using an 0.4% solution of trypan blue in PBS (Cellgro) in an automatic cell counter (Invitrogen) (38).…”

Section: Methodsmentioning

confidence: 99%

CDK9-Dependent Transcriptional Elongation in the Innate Interferon-Stimulated Gene Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells

Tian

Zhao

Kalita

et al. 2013

J Virol

Self Cite

View full text Add to dashboard Cite

The IL-6 Trans-Signaling-STAT3 Pathway Mediates ECM and Cellular Proliferation in Fibroblasts from Hypertrophic Scar

Cited by 99 publications

References 45 publications

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype

CDK9-Dependent Transcriptional Elongation in the Innate Interferon-Stimulated Gene Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells

Contact Info

Product

Resources

About