Journal
GLIA
Volume 60, Issue 12, Pages 1839-1859Publisher
WILEY
DOI: 10.1002/glia.22401
Keywords
cyclic AMP; phosphodiesterase; Rolipram; TNF-a; IL-1 ss; inflammation; CNS
Categories
Funding
- NINDS [056281, 056072]
- Miami Project to Cure Paralysis
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Cyclic AMP suppresses immune cell activation and inflammation. The positive feedback loop of proinflammatory cytokine production and immune activation implies that cytokines may not only be regulated by cyclic AMP but also conversely regulate cyclic AMP. This study examined the effects of tumor necrosis factor (TNF)-a and interleukin (IL)-1 beta on cyclic AMP-phosphodiesterase (PDE) signaling in microglia in vitro and after spinal cord injury (SCI) or traumatic brain injury (TBI). TNF-a or IL-1 beta stimulation produced a profound reduction (>90%) of cyclic AMP within EOC2 microglia from 30 min that then recovered after IL-1 beta but remained suppressed with TNF-a through 24 h. Cyclic AMP was also reduced in TNF-a-stimulated primary microglia, albeit to a lesser extent. Accompanying TNF-a-induced cyclic AMP reductions, but not IL-1 beta, 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-a; IL-1 beta increased all pde4 mRNAs. Immunoblotting for PDE4 showed that both cytokines increased PDE4A1, but only TNF-a increased PDE4B2. Immunocytochemistry revealed PDE4B nuclear translocation with TNF-a but not IL-1 beta. 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 24 h to 1 wk post-SCI, the peak of microglia activation. These studies show that TNF-a and IL-1 beta 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. (c) 2012 Wiley Periodicals, Inc.
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