Authors

Yang X, He G, Hao Y, Chen C, Li M, Wang Y, Zhang G, Yu Z. 2010. The role of the JAK2-STAT3 pathway in pro-inflammatory responses of EMF-stimulated N9 microglial cells. Journal of Neuroinflammation 7: 54.

Background
In several neuropathological conditions, such as Alzheimer’s disease, microglia can become overactivated and cause neurotoxicity. Previous studies have shown that exposure to electromagnetic fields (EMF) activates microglia to produce tumor necrosis factor (TNF)-α and nitric oxide (NO) through signal transduction involving Signal Transducer and Activator of Transcription (STAT).

Objective
The objective of this study was to investigate the role of STAT3 signaling in EMF-induced microglial activation and pro-inflammatory responses.

Methods
N9 microglial cells were treated with either an EMF exposure of 2.45 GHz (with a specific absorption rate of 6 W/kg) or a sham-treatment, with or without pretreatment with an inhibitor of the Janus family of tyrosine kinases (JAK), for 20 minutes. All exposures were conducted at a distance of 90 cm from the EMF source. The activation state of microglia was assessed by immunoreaction using a microglial marker, CD11b. Levels of inducible nitric oxide synthase (iNOS), TNF-α, and NO were measured using real-time reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, or the nitrate reductase method. Activation of JAKs and STAT3 proteins were evaluated by western blotting for specific tyrosine phosphorylation and the ability of STAT3 to bind to DNA was detected with an electrophoresis mobility shift assay.

Results
EMF exposure significantly induced the phosphorylation of JAK2 and STAT3, and the DNA-binding ability of STAT3 in N9 microglia. EMF exposure also significantly increased the expression of CD11b, TNF-α, and iNOS, and the production of NO. The JAK inhibitor strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF-stimulated microglia. Expression of CD11b, gene expression, and the production of TNF- α and iNOS were suppressed by the JAK inhibitor 12 hours after EMF exposure but not 3 hours after exposure.

Interpretation and Limitations
EMF exposure directly triggers initial activation of microglia and produces a significant proinflammatory response. Although some investigators have argued that EMF exposure does not lead to microglial activation at low SAR values, others have shown that the JAK-STAT
signaling pathway is involved in microglial activation. The findings of this study indicate that though the JAK2-STAT3 pathway may not mediate initial microglial activation, it does promote pro-inflammatory responses in EMF-stimulated microglial cells. The authors suggest that the JAK2-STAT3 pathway might be a therapeutic target for reducing pro-inflammatory responses in EMF-activated microglia. The limitations of this study are that it was conducted in vitro and effects may differ in vivo, and also many other physical factors such as infrasound exposure, irradiation, heat shock treatment and hyperthermia, can stimulate activation and pro-inflammatory reactions of microglia and these factors were not considered in this study.

Conclusions
This study suggests that the JAK2-STAT3 pathway may not mediate initial microglial activation, but does promote pro-inflammatory responses in EMF-stimulated microglial cells.


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