CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy
| Autor: | Edward H. Schuchman, Xingxuan He, Wiebke Hansen, Lukasz Japtok, Matthias Hose, Svenja Plöhn, Anja Eckstein, Utta Berchner-Pfannschmidt, Bärbel Edelmann |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Ceramide Acid Ceramidase T-Lymphocytes CD40 Ligand Sphingosine kinase Medizin Enzyme-Linked Immunosorbent Assay Mass Spectrometry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Sphingosine medicine Humans Sphingosine-1-phosphate CD40 Antigens Fluorescent Antibody Technique Indirect Inflammation Sphingolipids CD40 biology Fibroblasts Sphingolipid Molecular biology Graves Ophthalmopathy Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology Sphingomyelin Phosphodiesterase chemistry 030220 oncology & carcinogenesis biology.protein lipids (amino acids peptides and proteins) Acid sphingomyelinase Lysophospholipids 610 Medizin und Gesundheit Orbit medicine.drug Signal Transduction |
| Zdroj: | Investigative ophthalmologyvisual science. 59(13) |
| ISSN: | 1552-5783 |
| Popis: | PURPOSE. Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe; 1099 |
| Databáze: | OpenAIRE |
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