Nuclear factor-kappaB activation regulates cyclooxygenase-2 induction in human astrocytes in response to CXCL12: role in neuronal toxicity.
Neurodegenerative and neuroinflammatory disorders are commonly associated with local chemokine release. In other way, emerging data indicate that the prostaglandin E2 (PGE(2)), one of the major prostaglandins produced in the brain, play a central role in several pathological diseases. In this study, we investigated the relationship between CXCL12, cyclooxygenase (COX)-2 and PGE(2) in human brain cells. CXCL12 induced COX-2 and secretion of PGE(2) in a dose-dependent manner in human astrocytes. This induction was abolished by treatment with pertussis toxin and AMD3100, confirming the role of CXCR4 signaling. The nuclear factor-kappaB involvement was confirmed by using pyrrolidine dithiocarbamate, and with transient transfection assays. Over-expression of inhibitory proteins of nuclear factor-kappaB abrogated COX-2 induction, and CXCL12 induced p65/relA translocation. Culture supernatants from CXCL12-treated astrocytes reduced viability of neuroblastoma cells, and COX inhibitors abrogated this toxicity. Therefore, the relationship between chemokines and PGs could differentially influence the pathogenic network responsible for neurodegeneration.
Alvarez
Susana
S
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Blanco
Almudena
A
Fresno
Manuel
M
Muñoz-Fernández
M Angeles
MA
D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016328:NF-kappa B; D012333:RNA, Messenger; D008156:Luciferases; D051546:Cyclooxygenase 2; D015232:Dinoprostone