The anti-inflammatory activity of estrogen in glial cells is regulated by the PKC-anchoring protein RACK-1 |
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Authors: | Viviani Barbara Corsini Emanuela Binaglia Marco Lucchi Laura Galli Corrado L Marinovich Marina |
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Institution: | Centre of Excellence on Neurodegenerative Diseases and Laboratory of Toxicology, Department of Pharmacological Sciences, University of Milan, Milan, Italy. Barbara.Viviani@unimi.it |
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Abstract: | It has recently been suggested that estrogen inhibits glial activation and the release of neurotoxic mediators. The mechanisms involved in this anti-inflammatory effect are unclear. We found that an nM concentration of 17-beta estradiol inhibits protein kinaseC-betaII translocation induced by lipopolysaccharide in primary astrocytes. Estradiol treatment did not change the total content of kinaseC-betaII or of lipopolysaccharide receptor, but dose-dependently reduced the levels of receptors for activated C kinases-1 (RACK-1), the anchoring protein involved in protein kinase C (PKC) shuttling. This decrease could thus account for the defective protein kinaseC-betaII activation. Pre-treatment with 1 nmbeta-estradiol, which reduced by approximately 35% the expression of RACK-1, prevented the lipopolysaccharide-induced expression of tumour necrosis factor-alpha mRNA and of the inducible form of nitric oxide (NO) synthase. As a consequence, the production of tumour necrosis factor-alpha and NO were decreased. An antisense oligonucleotide for RACK-1 also reduced tumour necrosis factor-alpha and nitric oxide production on lipopolysaccharide stimulation. These results demonstrate that estrogen reduction of the RACK-1 expression, leading to a defective protein kinase-C activation counteracts the inflammatory response in astrocytes. |
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Keywords: | astrocytes β-estradiol inflammatory response protein kinase C βII receptors for activated C kinase-1 |
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