In:
Journal of Neurochemistry, Wiley, Vol. 134, No. 1 ( 2015-07), p. 125-134
Kurzfassung:
Microglia‐mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinson′s disease ( PD ), and a growing body of evidence indicates that onset and progression of PD correlates with the extent of neuroinflammatory responses involving Interferon γ ( IFN γ). Transforming growth factor β1 ( TGF 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 PD . In this study, we demonstrate that TGF β1 is able to block IFN γ‐induced microglia activation by attenuating STAT 1 phosphorylation and IFN γRα expression. Moreover, we identified a set of genes involved in microglial IFN γ signaling transduction that were significantly down‐regulated upon TGF β1 treatment, resulting in decreased sensitivity of microglia toward IFN γ stimuli. Interestingly, genes mediating negative regulation of IFN γ signaling, such as SOCS 2 and SOCS 6, were up‐regulated after TGF β1 treatment. Finally, we demonstrate that TGF β1 is capable of protecting midbrain dopaminergic ( mDA ) neurons from IFN γ‐driven neurotoxicity in mixed neuron‐glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of TGF β1 as a key immunoregulatory factor for microglia by silencing IFN γ‐mediated microglia activation and, thereby, rescuing mDA neurons from IFN γ‐induced neurotoxicity. image 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.
Materialart:
Online-Ressource
ISSN:
0022-3042
,
1471-4159
DOI:
10.1111/jnc.2015.134.issue-1
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2015
ZDB Id:
2020528-4
SSG:
12
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