Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury.
Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury.
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DOI：
10.1002/glia.22401
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发表时间：
2012-12
期刊：
影响因子：
6.2
通讯作者：
Pearse, Damien D.
中科院分区：
文献类型：
--
作者：
Ghosh, Mousumi;Garcia-Castillo, Daniela;Aguirre, Vladimir;Golshani, Roozbeh;Atkins, Coleen M.;Bramlett, Helen M.;Dietrich, W. Dalton;Pearse, Damien D.
环AMP抑制免疫细胞活化和炎症。促炎细胞因子产生和免疫激活的正反馈回路意味着细胞因子不仅可以被环AMP调节，而且可以反过来调节环AMP。本研究探讨了TNF-α和IL-1β对体外培养的小胶质细胞以及脊髓损伤或创伤性脑损伤（SCI，TBI）后小胶质细胞环腺苷酸磷酸二酯酶（cyclicAMP-phosphodiesterase，PDE）信号转导的影响。TNF-α或IL-1β刺激30 min后EOC 2小胶质细胞内cAMP水平显著降低（>90%），IL-1β刺激后恢复，但TNF-α刺激24 h后仍受到抑制。在TNF-α刺激的原代小胶质细胞中，环AMP也减少，尽管程度较低。伴随TNF-α诱导的环AMP减少，而不是IL-1β，环AMP-PDE活性增加。PDE 4活性在环AMP减少中的作用通过使用Rolipram证实。对pde 4 mRNA的检查显示，TNF-α可立即持续增加pde 4 b; IL-1β可增加所有pde 4 mRNA。PDE 4的免疫印迹显示，两种细胞因子都增加了PDE 4A 1，但只有TNF-α增加了PDE 4 B2。免疫细胞化学显示PDE 4 B与TNF-α发生核转位，但与IL-1β无关。急性SCI/TBI后，环AMP水平降低，PDE 4 B定位于活化的OX-42+小胶质细胞; PDE 4 B不存在于未损伤的脊髓/皮质或非活性小胶质细胞中的OX-42+细胞中。免疫印迹显示，PDE 4 B2在SCI后24 h至1 wk上调，这是小胶质细胞活化的高峰。这些研究表明，TNF-α和IL-1β对小胶质细胞中的环AMP-PDE信号传导有不同的影响。靶向PDE 4 B2可能是减少CNS损伤和神经退行性疾病中小胶质细胞活化的公认治疗方向。
Cyclic AMP suppresses immune cell activation and inflammation. The positive feedback loop of pro-inflammatory cytokine production and immune activation implies that cytokines may not only be regulated by cyclic AMP but conversely regulate cyclic AMP. This study examined the effects of TNF-α and IL-1β on cyclic AMP-phosphodiesterase (PDE) signaling in microglia in vitro and after spinal cord or traumatic brain injury (SCI, TBI). TNF-α or IL-1β stimulation produced a profound reduction (>90%) of cyclic AMP within EOC2 microglia from 30min that then recovered after IL-1β but remained suppressed with TNF-α through 24h. Cyclic AMP was also reduced in TNF-α-stimulated primary microglia, albeit to a lesser extent. Accompanying TNF-α-induced cyclic AMP reductions, but not IL-1β, was increased cyclic AMP-PDE activity. The role of PDE4 activity in cyclic AMP reductions was confirmed by using Rolipram. Examination of pde4 mRNA revealed an immediate, persistent increase in pde4b with TNF-α; IL-1β increased all pde4 mRNAs. Immunoblotting for PDE4 showed that both cytokines increased PDE4A1, but only TNF-α increased PDE4B2. Immunocytochemistry revealed PDE4B nuclear translocation with TNF-α but not IL-1β. Acutely after SCI/TBI, where cyclic AMP levels are reduced, PDE4B was localized to activated OX-42+ microglia; PDE4B was absent in OX-42+ cells in uninjured spinal cord/cortex or inactive microglia. Immunoblotting showed PDE4B2 up-regulation from 24h to 1wk post-SCI, the peak of microglia activation. These studies show that TNF-α and IL-1β differentially affect cyclic AMP-PDE signaling in microglia. Targeting PDE4B2 may be a putative therapeutic direction for reducing microglia activation in CNS injury and neurodegenerative diseases.
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