Astrocytes, but not microglia, rapidly sense H 2O 2 via STAT6 phosphorylation, resulting in cyclooxygenase-2 expression and prostaglandin release
- 등재 SCIE, SCOPUS
- 발행기관 American Association of Immunologists
- 발행년도 2012
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000093607
- 본문언어 영어
- Published As http://dx.doi.org/10.4049/jimmunol.1101600
초록/요약
Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood-brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H 2O 2 by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src-JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H 2O 2-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H 2O 2 did not affect astrocyte viability, H 2O 2-induced STAT6 phosphorylation resulted in STAT6- dependent cyclooxygenase-2 expression and subsequent release of PGE2 and prostacyclin, an effect also observed in hypoxia/ reoxygenation. Finally, PGs released from H 2O 2-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H 2O 2 suggest that astrocytes can act as sentinels for certain stimuli, including H 2O 2 and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli. Copyright©2012 by The American Association of Immunologists, Inc.
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