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- Title
Modulation of microglial superoxide production by α-tocopherol in vitro: attenuation of p67[sup phox] translocation by a protein phosphatase-dependent pathway.
- Authors
Egger, T.; Hammer, A.; Wintersperger, A.; Goti, D.; Malle, E.; Sattler, W.
- Abstract
As in other phagocytic cells, the NADPH-oxidase system in microglia is thought to be primarily responsible for the production of superoxide anion radicals (O[sub 2][sup -]·), a potentially cytotoxic reactive oxygen species. The assembly of a functional NADPH-oxidase complex at the plasma membrane depends on the phosphorylation and subsequent translocation of several cytosolic subunits. Immunocytochemical and subcellular fractionation experiments performed during the present study revealed that the NADPH-oxidase subunit p67[sup phox] translocates from the cytosol to the plasma membrane upon stimulation. Pre-incubation of microglia in α-tocopherol (αTocH) containing medium decreased O[sub 2][sup -]· production in a time- and concentration-dependent manner, findings attributed to attenuated p67[sup phox] translocation to the plasma membrane. Moreover, αTocH-supplementation of the culture medium resulted in decreased microglial protein kinase C (PKC) activities, an effect that could be partially or completely reversed by the addition of protein phosphatase inhibitors (okadaic acid and calyculin A). The addition of the PKC-inhibitor staurosporine inhibited the microglial respiratory burst in a manner comparable to αTocH. The addition of okadaic acid or calyculin A completely restored O[sub 2][sup -]· production in αTocH-supplemented cells. The present findings suggest that αTocH inactivates PKC via a PP1 or PP2A-mediated pathway and, as a consequence, blocks the phosphorylation-dependent translocation of p67[sup phox] to the plasma membrane. As a result, O[sub 2][sup -]· production by the microglial NADPH-oxidase system is substantially inhibited.
- Subjects
MICROGLIA; SUPEROXIDES
- Publication
Journal of Neurochemistry, 2001, Vol 79, Issue 6, p1169
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1046/j.1471-4159.2001.00641.x