TY  - GEN
A1  - Plöhn, Svenja
A1  - Edelmann, Bärbel
A1  - Japtok, Lukasz
A1  - He, Xingxuan
A1  - Hose, Matthias
A1  - Hansen, Wiebke
A1  - Schuchman, Edward H.
A1  - Eckstein, Anja
A1  - Berchner-Pfannschmidt, Utta
T1  - CD40 enhances sphingolipids in orbital fibroblasts
BT  - potential role of sphingosine-1-phosphate in inflammatory T-cell migration in Graves' orbitopathy
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1099 
KW  - Grave’s orbitopathy
KW  - sphingosine-1-phosphate
KW  - sphingolipids
KW  - inflammation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468837
SN  - 1866-8372
IS  - 1099
ER  - 
TY  - JOUR
A1  - Plöhn, Svenja
A1  - Edelmann, Bärbel
A1  - Japtok, Lukasz
A1  - He, Xingxuan
A1  - Hose, Matthias
A1  - Hansen, Wiebke
A1  - Schuchman, Edward H.
A1  - Eckstein, Anja
A1  - Berchner-Pfannschmidt, Utta
T1  - CD40 enhances sphingolipids in orbital fibroblasts
BT  - potential role of sphingosine-1-phosphate in inflammatory T-Cell migration in graves' orbitopathy
JF  - Investigative ophthalmology & visual science
N2  - 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.
KW  - inflammation
Y1  - 2018
U6  - https://doi.org/10.1167/iovs.18-25466
SN  - 0146-0404
SN  - 1552-5783
VL  - 59
IS  - 13
SP  - 5391
EP  - 5397
PB  - Association for Research in Vision and Opthalmology
CY  - Rockville
ER  -