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Medientyp:
E-Artikel
Titel:
TGFβ1 inhibits IFNγ‐mediated microglia activation and protects mDA neurons from IFNγ‐driven neurotoxicity
Beteiligte:
Zhou, Xiaolai;
Zöller, Tanja;
Krieglstein, Kerstin;
Spittau, Björn
Erschienen:
Wiley, 2015
Erschienen in:Journal of Neurochemistry
Sprache:
Englisch
DOI:
10.1111/jnc.13111
ISSN:
0022-3042;
1471-4159
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Microglia‐mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinson′s disease (<jats:styled-content style="fixed-case">PD</jats:styled-content>), and a growing body of evidence indicates that onset and progression of <jats:styled-content style="fixed-case">PD</jats:styled-content> correlates with the extent of neuroinflammatory responses involving Interferon γ (<jats:styled-content style="fixed-case">IFN</jats:styled-content>γ). Transforming growth factor β1 (<jats:styled-content style="fixed-case">TGF</jats:styled-content>β1) has been shown to be a major player in the regulation of microglia activation states and functions and, thus, might be a potential therapeutic agent by shaping microglial activation phenotypes during the course of neurodegenerative diseases such as <jats:styled-content style="fixed-case">PD</jats:styled-content>. In this study, we demonstrate that <jats:styled-content style="fixed-case">TGF</jats:styled-content>β1 is able to block <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ‐induced microglia activation by attenuating <jats:styled-content style="fixed-case">STAT</jats:styled-content>1 phosphorylation and <jats:styled-content style="fixed-case">IFN</jats:styled-content>γRα expression. Moreover, we identified a set of genes involved in microglial <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ signaling transduction that were significantly down‐regulated upon <jats:styled-content style="fixed-case">TGF</jats:styled-content>β1 treatment, resulting in decreased sensitivity of microglia toward <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ stimuli. Interestingly, genes mediating negative regulation of <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ signaling, such as <jats:styled-content style="fixed-case">SOCS</jats:styled-content>2 and <jats:styled-content style="fixed-case">SOCS</jats:styled-content>6, were up‐regulated after <jats:styled-content style="fixed-case">TGF</jats:styled-content>β1 treatment. Finally, we demonstrate that <jats:styled-content style="fixed-case">TGF</jats:styled-content>β1 is capable of protecting midbrain dopaminergic (<jats:styled-content style="fixed-case">mDA</jats:styled-content>) neurons from <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ‐driven neurotoxicity in mixed neuron‐glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of <jats:styled-content style="fixed-case">TGF</jats:styled-content>β1 as a key immunoregulatory factor for microglia by silencing <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ‐mediated microglia activation and, thereby, rescuing <jats:styled-content style="fixed-case">mDA</jats:styled-content> neurons from <jats:styled-content style="fixed-case">IFN</jats:styled-content>γ‐induced neurotoxicity.
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Interferon γ (IFNγ) is a potent pro‐inflammatory factor that triggers the activation of microglia and the subsequent release of neurotoxic factors. Transforming growth factor β1 (TGFβ1) is able to inhibit the IFNγ‐mediated activation of microglia, which is characterized by the release of nitric oxide (NO) and tumor necrosis factor α (TNFα). By decreasing the expression of IFNγ‐induced genes as well as the signaling receptor IFNγR1, TGFβ1 reduces the responsiveness of microglia towards IFNγ. In mixed neuron‐glia cultures, TGFβ1 protects midbrain dopaminergic (mDA) neurons from IFNγ‐induced neurotoxicity.</jats:p>