NF-kappaB induces PGE2-synthesizing enzymes in neurons.
The transcription factor NF-kappaB is activated in neurons and promotes neuronal death in cerebral ischemia. Its target genes include cytosolic phospholipase A-2 (cPLA-2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E(2) synthase-1 (mPGES-1), three genes that are involved in the synthesis of prostaglandin E(2) (PGE(2)). In our study, oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia, activated NF-kappaB activity in primary cortical neurons. Furthermore, OGD and the NF-kappaB activator tumor necrosis factor stimulated the expression of cPLA-2, cyclooxygenase-2 (COX-2), and mPGES-1 and increased the release of PGE(2) from neurons. Expression of a constitutively active IkappaB kinase (IKK) or the NF-kappaB subunit p65 in neurons stimulated the transcription of cPLA-2, COX-2, and mPGES-1. Finally, inhibition of IKK in neurons blocked the induction of the three genes involved in PGE(2) synthesis in vivo. In summary, NF-kappaB controls the neuronal expression of three genes involved in PGE(2) synthesis in cerebral ischemia.
Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.
Waleed
W
Barakat
Oliver
O
Herrmann
Bernd
B
Baumann
Markus
M
Schwaninger
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D015687:Cell Hypoxia; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000502:physiology; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D051550:I-kappa B Kinase / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000235:genetics; D000071876:Prostaglandin-E Synthases
D016328:NF-kappa B; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D054510:Phospholipases A2, Cytosolic; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D005947:Glucose; D015232:Dinoprostone