Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor β-Dependent Fibroblast Activation

2016 ◽  
Vol 68 (8) ◽  
pp. 1989-2002 ◽  
Author(s):  
Feng Fang ◽  
Roberta Goncalves Marangoni ◽  
Xingchun Zhou ◽  
Yang Yang ◽  
Boping Ye ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Toll Like Receptor ◽  
Fibroblast Activation

scholarly journals Expression of transforming growth factor β receptor II in mesenchymal stem cells from systemic sclerosis patients

BMJ Open ◽  
2013 ◽  
Vol 3 (1) ◽  
pp. e001890 ◽  
Author(s):  
Valérie Vanneaux ◽  
Dominique Farge-Bancel ◽  
Séverine Lecourt ◽  
Julie Baraut ◽  
Audrey Cras ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Systemic Sclerosis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Β Receptor

scholarly journals Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF

2017 ◽  
Vol 312 (1) ◽  
pp. L42-L55 ◽  
Author(s):  
Simone Ebener ◽  
Sandra Barnowski ◽  
Carlos Wotzkow ◽  
Thomas M. Marti ◽  
Elena Lopez-Rodriguez ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Lung Fibroblasts ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Vitro Model ◽  
Fibroblast Foci

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a median survival of 3 yr. IPF deteriorates upon viral or bacterial lung infection although pulmonary infection (pneumonia) in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in IPF fibroblasts. Lung tissue sections from patients with IPF were analyzed for TLR4 expression. Isolated normal human lung fibroblasts (NL-FB) and IPF fibroblasts (IPF-FB) were exposed to LPS and transforming growth factor-β (TGF-β) before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of IPF lungs as well as in primary NL-FB and IPF-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and IPF-FB were coexposed to LPS and TGF-β. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-β stimulation alone, IPF-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-β receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and IPF fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.

scholarly journals Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment

2017 ◽  
Vol 44 (5) ◽  
pp. 631-638 ◽  
Author(s):  
D. James Haddon ◽  
Hannah E. Wand ◽  
Justin A. Jarrell ◽  
Robert F. Spiera ◽  
Paul J. Utz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Systemic Sclerosis ◽  
Growth Factor ◽  
Clinical Improvement ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Transforming Growth Factor Β ◽  
Elastic Net ◽  
Open Label ◽  
Link Type

Objective.Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.Methods.We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.Results.The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.Conclusion.Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.govNCT00555581 and NCT01166139.

scholarly journals Transforming growth factor- β -induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts

2016 ◽  
Vol 7 ◽  
pp. 246-252 ◽  
Author(s):  
Tetsurou Ikeda ◽  
Maria Fragiadaki ◽  
Xu Shi-wen ◽  
Markella Ponticos ◽  
Korsa Khan ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts
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