ArticleThe Journal of biological chemistry2013
Sphingosine 1-phosphate (S1P) receptor agonists mediate pro-fibrotic responses in normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent signaling.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 98 citations in OpenAlex.
- Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial.Journal of neurology, neurosurgery, and psychiatry · 2014Trial
- Molecular characteristics of apolipoprotein M and its biological functions in kidney diseases.Molecular and cellular biochemistry · 2026Review
- Deep phenotyping of skin tissue remodeling in patients with systemic sclerosis treated with CD19-CAR T cells.Nature communications · 2026Article
- Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review).Molecular medicine reports · 2026Review
- Review
- Macrophage migration inhibitory factor mediates joint capsule fibrosis via facilitating phospholipid metabolite PGE2 production in fibroblasts.Cellular and molecular life sciences : CMLS · 2025Article
- Inhibition of sphingosine 1-phosphate receptor 3 ameliorates bleomycin-induced pulmonary fibrosis by suppressing macrophage M2 polarization.Genes & diseases · 2025Article
- Role of Sphingosine-1-Phosphate Signaling Pathway in Pancreatic Diseases.International journal of molecular sciences · 2024Review
- Positive and negative feedback regulation of the TGF-β1 explains two equilibrium states in skin aging.iScience · 2024Article
- Review
- Down-regulation of key regulatory factors in sphingosine-1-phosphate (S1P) pathway in human lung fibroblasts transfected with selected microRNAs.Molecular biology research communications · 2024Article
- The Sphingosine 1-Phosphate Axis: an Emerging Therapeutic Opportunity for Endometriosis.Reproductive sciences (Thousand Oaks, Calif.) · 2023Review
- The Role of Sphingolipids in Regulating Vascular Permeability in Idiopathic Pulmonary Fibrosis.Biomedicines · 2023Review
- Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge.International journal of molecular sciences · 2022Review
- Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis.American journal of respiratory cell and molecular biology · 2022Article
- Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage.Frontiers in physiology · 2021Review
- Review
- Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways.International journal of molecular sciences · 2020Review
- Detrimental role of sphingosine kinase 1 in kidney damage in DOCA-salt hypertensive model: evidence from knockout mice.BMC nephrology · 2020Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Synthetic sphingosine 1-phosphate receptor 1 modulators constitute a new class of drugs for the treatment of autoimmune diseases. Sphingosine 1-phosphate (S1P) signaling, however, is also involved in the development of fibrosis. Using normal human lung fibroblasts, we investigated the induction of fibrotic responses by the S1P receptor (S1PR) agonists S1P, FTY720-P, ponesimod, and SEW2871 and compared them with the responses induced by the known fibrotic mediator TGF-β1. In contrast to TGF-β1, S1PR agonists did not induce expression of the myofibroblast marker α-smooth muscle actin. However, TGF-β1, S1P, and FTY720-P caused robust stimulation of extracellular matrix (ECM) synthesis and increased pro-fibrotic marker gene expression including connective tissue growth factor. Ponesimod showed limited and SEW2871 showed no pro-fibrotic potential in these readouts. Analysis of pro-fibrotic signaling pathways showed that in contrast to TGF-β1, S1PR agonists did not activate Smad2/3 signaling but rather activated PI3K/Akt and ERK1/2 signaling to induce ECM synthesis. The strong induction of ECM synthesis by the nonselective agonists S1P and FTY720-P was due to the stimulation of S1P2 and S1P3 receptors, whereas the weaker induction of ECM synthesis at high concentrations of ponesimod was due to a low potency activation of S1P3 receptors. Finally, in normal human lung fibroblast-derived myofibroblasts that were generated by TGF-β1 pretreatment, S1P and FTY720-P were effective stimulators of ECM synthesis, whereas ponesimod was inactive, because of the down-regulation of S1P3R expression in myofibroblasts. These data demonstrate that S1PR agonists are pro-fibrotic via S1P2R and S1P3R stimulation using Smad-independent pathways.
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