- 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 elevatedPURPOSE. 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.…
MetadatenAuthor details: | Svenja Plöhn, Bärbel Edelmann, Lukasz JaptokGND, Xingxuan He, Matthias HoseGND, Wiebke HansenGND, Edward H. Schuchman, Anja Eckstein, Utta Berchner-PfannschmidtGND |
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URN: | urn:nbn:de:kobv:517-opus4-468837 |
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DOI: | https://doi.org/10.25932/publishup-46883 |
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ISSN: | 1866-8372 |
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Title of parent work (German): | Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe |
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Subtitle (English): | potential role of sphingosine-1-phosphate in inflammatory T-cell migration in Graves' orbitopathy |
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Publication series (Volume number): | Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (1099) |
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Publication type: | Postprint |
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Language: | English |
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Date of first publication: | 2021/01/15 |
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Publication year: | 2018 |
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Publishing institution: | Universität Potsdam |
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Release date: | 2021/01/15 |
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Tag: | Grave’s orbitopathy; inflammation; sphingolipids; sphingosine-1-phosphate |
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Issue: | 1099 |
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Number of pages: | 9 |
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Source: | Investigative Ophthalmology & Visual Science 59 (2018) 13, Art. 5392 DOI: 10.1167/iovs.18-25466 |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät |
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| Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Peer review: | Referiert |
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Publishing method: | Open Access / Green Open-Access |
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License (German): | CC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International |
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External remark: | Bibliographieeintrag der Originalveröffentlichung/Quelle |
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