Sphingosine-1-phosphate: A Janus-faced mediator of fibrotic diseases |
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Authors: | Stephanie Schwalm Josef Pfeilschifter Andrea Huwiler |
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Institution: | 1. Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt am Main, Germany;2. Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3011 Bern, Switzerland |
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Abstract: | Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that acts either on G protein-coupled S1P receptors on the cell surface or via intracellular target sites. In addition to the well established effects of S1P in angiogenesis, carcinogenesis and immunity, evidence is now continuously accumulating which demonstrates that S1P is an important regulator of fibrosis. The contribution of S1P to fibrosis is of a Janus-faced nature as S1P exhibits both pro- and anti-fibrotic effects depending on its site of action. Extracellular S1P promotes fibrotic processes in a S1P receptor-dependent manner, whereas intracellular S1P has an opposite effect and dampens a fibrotic reaction by yet unidentified mechanisms. Fibrosis is a result of chronic irritation by various factors and is defined by an excess production of extracellular matrix leading to tissue scarring and organ dysfunction. In this review, we highlight the general effects of extracellular and intracellular S1P on the multistep cascade of pathological fibrogenesis including tissue injury, inflammation and the action of pro-fibrotic cytokines that stimulate ECM production and deposition. In a second part we summarize the current knowledge about the involvement of S1P signaling in the development of organ fibrosis of the lung, kidney, liver, heart and skin. Altogether, it is becoming clear that targeting the sphingosine kinase-1/S1P signaling pathway offers therapeutic potential in the treatment of various fibrotic processes. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. |
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Keywords: | BAL bronchoalveolar lavage BMSC bone marrow-derived stem cell CCl4 carbon tetrachloride Col collagen CTGF connective tissue growth factor DN diabetic nephropathy EC epithelial cell ERK extracellular signal-regulated kinase FB fibroblast FN fibronectin HSC hepatic stellate cell IPF idiopathic pulmonary fibrosis iS1P intracellular sphingosine-1-phosphate JNK c-Jun N-terminal kinase LDL low density lipoprotein PDGF platelet-derived growth factor PPAR peroxisome proliferator-activated receptor PPM1A protein phosphatase 1A PTEN phosphatase and tensin homolog S1P sphingosine-1-phosphate α-SMA α-smooth muscle actin SphK sphingosine kinase SSc systemic scleroderma TGF-β transforming growth factor β Vim vimentin WT wild-type |
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