Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay Between Proinflammatory and Anti-inflammatory Signals.
From: Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones CientÃficas, Madrid, Spain.
The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publish Date: Aug 2007
- ISSN: 1529-2401
- Volume: 27
- Issue: 33
- Pages: 8745-56
- Medium: Internet
- Language: English
- Citation (JAMA): Fernandez Ana M, Fernandez Silvia, Carrero Paloma, et al. Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay Between Proinflammatory and Anti-inflammatory Signals.. J. Neurosci. Aug 2007;27:8745-56
Abstract
Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor kappaB (NFkappaB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti-inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFkappaB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-alpha or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression.
Mesh Headings (Keywords): Animals, Animals, Newborn, Astrocytes, Brain Injuries, Calcineurin, Cells, Cultured, Drug Interactions, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Inflammation, Insulin-Like Growth Factor I, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Protein-Serine-Threonine Kinases, RNA, Messenger, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tumor Necrosis Factor-alpha
Check for Full Text / PubMed Unique Identifier (PMID): 17699657
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