この研究は、著者の以前の研究の結果を受けて、電磁界（EMF）によるミクログリア活性化と炎症反応におけるSTAT3シグナル伝達の役割をより詳しく調査した。N9ミクログリア細胞を、Janus型チロシンキナーゼ（JAK）の阻害薬（ピリドン6、P6）による前処理の有無とEMFばく露（マイクロ波パルス；SAR 6W/kg）または擬似ばく露の組合せによる4群に分け、ミクログリアマーカーCD11bによる免疫反応状態、誘導型一酸化窒素シンターゼ(iNOS)、TNF-α、NOのレベル、JAKとSTAT3蛋白質の活性化、STAT3のDNA結合能を測定した。その結果、EMF群ではJAK2とSTAT3のリン酸化反応ならびにN9ミクログリア中のSTAT3のDNA結合能が著しく高められた；さらにEMF群ではCD11b、TNF-α、iNOSの発現とNOの生成が劇的に増加した；P6処置群ではJAK2およびSTAT3のリン酸化反応が強く抑制され、その後のEMFばく露によりミクログリア中のSTAT3の活性がなくなった；CD11bの発現ならびにTNF-αおよびiNOSの遺伝子発現・生成のP6による抑制は、EMFばく露後12時間では見られたが、3時間では見られなかった、と報告している。
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To study, in more detail than in a previous study (Hao et al. 2010), the activation of microglia and involvement of signal transducer and activator of transcription 3 (STAT3; mediates signal transduction from the extracellular environment to the nucleus) in microglia activation after 2.45 GHz electromagnetic fields exposure.
Microglia is considered as a specialised macrophages residing form in the central nervous system. In response to a variety of insults, microglia adopts an activated phenotype. Microglia activation plays a pivotal role in the initiation and progression of several neurodegenerative diseases.
Some cell samples were pretreated with the JAK inhibitor pyridone 6 (P6) to study whether P6 could affect the STAT3 activation (to further demonstrate JAK2-STAT3 signal transduction (JAK is a STAT3 activator and is able to phosphorylate STAT3)). Cells were investigated 1 h, 3 h, 6 h, 12 h, and 24 h after exposure.
A part of the cells were pretreated with Pyridone 6
| 周波数 | 2.45 GHz |
|---|---|
| タイプ |
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| ばく露時間 | continuous for 20 min |
| Modulation type | pulsed |
|---|---|
| Pulse width | 2 µs |
| Packets per second | 500 |
| ばく露の発生源／構造 |
|
|---|---|
| Distance between exposed object and exposure source | 90 cm |
| チャンバの詳細 | anechoic chamber with a temperature of 25° C - 26° C |
| ばく露装置の詳細 | four flasks placed in a 24.5 cm x 21 cm water bath at 37° C; irradiation directed downward from the rectangular horn antenna to the flasks by a refector |
| Sham exposure | A sham exposure was conducted. |
The data showed that the electromagnetic field exposure significantly induced the phosphorylation of JAK2 and STAT3 (time-dependent manner with peak at 12 h), and the DNA-binding ability of STAT3 in N9 microglia. Additionally, electromagnetic field exposure dramatically increased the expression of CD11b, tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS), and the production of nitric oxide.
P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and decreased the STAT3 activity in electromagnetic field-stimulated microglia. Interestingly, expression of CD11b as well as gene expression and production of tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) were suppressed by P6 at 12 h, but not at 3 h after electromagnetic field exposure.
In conclusion, the electromagnetic field exposure directly triggered an initial activation of microglia and produced a significant pro-inflammatory response. Activation of JAK2-STAT3 signaling occured in parallel with the microglial activation and the release of pro-inflammatory factors (i.e. tumor necrosis factor-alpha, iNOS and nitric oxide). Microglia activation and pro-inflammatory responses were significantly reduced by P6 at 12 h, but not at 3 h after electromagnetic field exposure. These data suggest that the JAK2-STAT3 pathway may not mediate the initial microglial activation but does promote pro-inflammatory responses in electromagnetic field-stimulated microglial cells. The data provide a basis to determine whether the pro-inflammatory responses of electromagnetic field-stimulated microglia can be suppressed by inhibition of the JAK2-STAT3 pathway in therapeutic interventions.
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