Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia

• Published in: Biochemical journal Vol. 370; no. Pt 2; pp. 459 - 467
• Main Authors: Egger, Tamara, Schuligoi, Rufina, Wintersperger, Andrea, Amann, Rainer, Malle, Ernst, Sattler, Wolfgang
• Format: Journal Article
• Language: English
• Published: England 01.03.2003
• Subjects: Animals; Cell Line, Transformed; Cyclooxygenase 2; Dinoprostone - metabolism; Enzyme Activation - physiology; Isoenzymes - biosynthesis; Isoenzymes - drug effects; Isoenzymes - genetics; Lipopolysaccharides - metabolism; Mice; Microglia - drug effects; Microglia - metabolism; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; Phosphoprotein Phosphatases - metabolism; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - drug effects; Prostaglandin-Endoperoxide Synthases - genetics; Protein Phosphatase 2; Vitamin E - metabolism; Vitamin E - pharmacology
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj20021358

One of the immediate early microglial genes that are up-regulated in response to proinflammatory stimuli is cyclo-oxygenase 2 (COX-2). In the present study, we have investigated the effects of alpha-tocopherol (alpha TocH), an essential constituent of the nervous system, on the activation of COX-2 in lipopolysaccharide (LPS)-stimulated mouse BV-2 microglia. In unstimulated BV-2 cells, COX-2 mRNA and protein were almost undetectable but were strongly up-regulated in response to LPS. Activation of COX-2 protein synthesis in LPS-stimulated BV-2 cells involved activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathway and was sensitive to the protein kinase C (PKC) inhibitors staurosporine and chelerythrine, and the MAP kinase/ERK kinase 1/2 inhibitors PD98059 and U0126. Supplementation of BV-2 cells with alpha TocH before LPS stimulation resulted in pronounced up-regulation of protein phosphatase 2A (PP2A) activity, down-regulation of PKC activity, ERK1/2 phosphorylation and nuclear factor kappa B (NF kappa B) activation. As a result, COX-2 protein levels and prostaglandin E(2) production were significantly lower in alpha TocH-supplemented cells. The effects of alpha TocH on PKC activity could be reverted by calyculin A and okadaic acid, two PP inhibitors. In summary, our results suggest that alpha TocH activates microglial PP2A activity and thereby silences an LPS-activated PKC/ERK/NF kappa B signalling cascade resulting in significantly attenuated COX-2 protein synthesis. These in vitro results imply that alpha TocH could induce quiescence to pathways that are associated with acute or chronic inflammatory conditions in the central nervous system.