The anti-inflammatory activity of estrogen in glial cells is regulated by the PKC-anchoring protein RACK-1.
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.
Viviani
Barbara
B
Centre of Excellence on Neurodegenerative Diseases and Laboratory of Toxicology, Department of Pharmacological Sciences, University of Milan, Milan, Italy. Barbara.Viviani@unimi.it
Corsini
Emanuela
E
Binaglia
Marco
M
Lucchi
Laura
L
Galli
Corrado L
CL
Marinovich
Marina
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004967:Estrogens; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011493:Protein Kinase C; D064546:Protein Kinase C beta