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http://doi.org/10.25358/openscience-7927
Autoren: | Trinschek, Bettina Lüssi, Felix Haas, Jürgen Wildemann, Brigitte Zipp, Frauke Wiendl, Heinz Becker, Christian Jonuleit, Helmut |
Titel: | Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis |
Online-Publikationsdatum: | 10-Okt-2022 |
Erscheinungsdatum: | 2013 |
Sprache des Dokuments: | Englisch |
Zusammenfassung/Abstract: | In multiple sclerosis (MS) autoaggressive T effector cells (Teff) are not efficiently controlled by regulatory T cells (Treg) but the underlying mechanisms are incompletely understood. Proinflammatory cytokines are key factors facilitating Teff activity in chronic inflammation. Here we investigated the influence of IL-6 on Treg sensitivity of Teff from therapy-naïve MS patients with or without active disease. Compared to healthy volunteers and independent of disease course CD4 and especially CD8 MS-Teff were insensitive against functional active Treg from healthy controls. This unresponsiveness was caused by accelerated production of IL-6, elevated IL-6 receptor expression and phosphorylation of protein kinase B (PKB)/c-Akt in MS-Teff. In a positive feedback loop, IL-6 itself induced its accelerated synthesis and enhanced phosphorylation of PKB/c-Akt that finally mediated Treg resistance. Furthermore, accelerated IL-6 release especially by CD8 Teff prevented control of surrounding Teff, described here as bystander resistance . Blockade of IL-6 receptor signaling or direct inhibition of PKB/c-Akt phosphorylation restored Treg responsiveness of Teff and prevented bystander resistance. In Teff of healthy controls (HC) exogenous IL-6 also changed the kinetics of IL-6 production and induced Treg unresponsiveness. This modulation was only transient in Teff from healthy volunteers, whereas accelerated IL-6 production in MS-Teff maintained also in absence of IL-6. Hence, we showed that the kinetics of IL-6 production instead of elevated IL-6 levels defines the Teff responsiveness in early Treg-T cell communication in MS independent of their disease course and propose IL-6 and associated PKB/c-Akt activation as effective therapeutic targets for modulation of Teff activity in MS. |
DDC-Sachgruppe: | 610 Medizin 610 Medical sciences |
Veröffentlichende Institution: | Johannes Gutenberg-Universität Mainz |
Organisationseinheit: | FB 04 Medizin |
Veröffentlichungsort: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7927 |
Version: | Published version |
Publikationstyp: | Zeitschriftenaufsatz |
Nutzungsrechte: | CC BY |
Informationen zu den Nutzungsrechten: | https://creativecommons.org/licenses/by/3.0/ |
Zeitschrift: | Plos one 8 10 |
Seitenzahl oder Artikelnummer: | e77634 |
Verlag: | PLoS |
Verlagsort: | Lawrence, Kan. |
Erscheinungsdatum: | 2013 |
ISSN: | 1932-6203 |
URL der Originalveröffentlichung: | http://dx.doi.org/10.1371/journal.pone.0077634 |
DOI der Originalveröffentlichung: | 10.1371/journal.pone.0077634 |
Enthalten in den Sammlungen: | DFG-OA-Publizieren (2012 - 2017) |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | ||
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kinetics_of_il6_production_de-20220924212016766.pdf | 2.12 MB | Adobe PDF | Öffnen/Anzeigen |