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IL\u201033 is released from necrotic endothelial cells and contributes to MS severity by coactivating\u00a0T cells. Herein we analyzed the influence of FTY720, FTY720\u2010P, and S1P on IL\u201033 induced formation of IL\u20102 and IFN\u2010<jats:bold>\u03b3<\/jats:bold>, by using IL\u201033 receptor overexpressing EL4 cells, primary CD8<jats:bold><jats:sup>+<\/jats:sup><\/jats:bold> T cells, and splenocytes. EL4\u2010ST2 cells released IL\u20102 after IL\u201033 stimulation that was inhibited dose\u2010dependently by FTY720\u2010P but not FTY720. In this system, S1P increased IL\u20102, and accordingly, inhibition of S1P producing sphingosine kinases diminished IL\u20102 release. In primary CD8<jats:bold><jats:sup>+<\/jats:sup><\/jats:bold> T cells and splenocytes IL\u201033\/IL\u201012 stimulation induced IFN\u2010<jats:bold>\u03b3<\/jats:bold>, which was prevented by FTY720 but not FTY720\u2010P, independently from intracellular phosphorylation. The inhibition of IFN\u2010<jats:bold>\u03b3<\/jats:bold> by nonphosphorylated FTY720 was mediated via the SET\/protein phosphatase 2A (PP2A) pathway, since a SET peptide antagonist also prevented IFN\u2010<jats:bold>\u03b3<\/jats:bold> formation and the inhibition of IFN\u2010<jats:bold>\u03b3<\/jats:bold> by FTY720 was reversible by a PP2A inhibitor. While our findings directly improve the understanding of FTY720 therapy in MS, they could also contribute to side effects of FTY720 treatment, like progressive multifocal leukoencephalopathy, caused by an insufficient immune response to a viral infection.<\/jats:p>","DOI":"10.1002\/eji.201545805","type":"journal-article","created":{"date-parts":[[2015,12,18]],"date-time":"2015-12-18T18:14:48Z","timestamp":1450462488000},"page":"941-951","source":"Crossref","is-referenced-by-count":15,"title":["Fingolimod targeting protein phosphatase 2A differently affects IL\u201033 induced IL\u20102 and IFN\u2010\u03b3 production in CD8<sup>+<\/sup> lymphocytes"],"prefix":"10.1002","volume":"46","author":[{"given":"Florian","family":"Ottenlinger","sequence":"first","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Schwiebs","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Pfarr","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Wagner","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Gr\u00fcner","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph A.","family":"Mayer","sequence":"additional","affiliation":[{"name":"Center for Neurology and Neurosurgery Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinfried H.","family":"Radeke","sequence":"additional","affiliation":[{"name":"pharmazentrum frankfurt\/ZAFES Hospital of the Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3248"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2011.02.007"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049427"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)01168-2"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.171116"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.064162"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200176200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510389178"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0910fje"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311743200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2014.03.002"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2015.1093620"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12238"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201201283"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-492181"},{"key":"e_1_2_7_17_1","first-page":"388","article-title":"Regulation of PP2A by sphingolipid metabolism and signaling","volume":"4","author":"Oaks J.","year":"2014","journal-title":"Front. 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