Interleukin-1beta induced cyclooxygenase 2 expression and prostaglandin E2 secretion by human neuroblastoma cells: implications for Alzheimer's disease.
Non-steroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of developing Alzheimer's disease (AD). Cyclooxygenase 2 (COX-2), one of the targets of NSAIDs, is increasingly expressed in neuronal cells in AD brain. In this study, of the cytokines that are found at increased levels in AD brain (interleukin (IL)-1alpha, IL-1beta, IL-6 and tumour necrosis factor (TNF)alpha), IL-1beta was found to induce COX-2 immunoreactivity and prostaglandin (PG) E2 secretion by human neuroblastoma cell line SK-N-SH. COX inhibitors indomethacin and BF389, as well as the glucocorticoid dexamethasone (DEX) and pyrrolidinedithiocarbamate, which is an inhibitor of nuclear factor kappaB as well as a potent antioxidant, inhibited IL-1beta induced PGE2 secretion. In addition, DEX reduced the IL-1beta induced COX-2 immunoreactivity in the same concentration as wherein it inhibited PGE2 secretion. Palmitoyl trifluormethyl ketone, an inhibitor of Ca(2+) independent phospholipase A2 (iPLA2) and a less potent inhibitor of cytosolic PLA2, dose-dependently reduced the IL-1beta induced PGE2 secretion. This suggests that the IL-1beta induced PGE2 secretion may depend on the availability of arachidonic acid. Although the physiological role of neuronal COX-2 still remains unclear, we suggest an interplay between glial derived IL-1 and neuronal upregulation of COX-2 expression in chronic neurodegenerative diseases, such as AD.
Department of Psychiatry, Research Institute Neurosciences Vrije Universiteit, Vrije Universiteit, Amsterdam, The Netherlands. jjm.hoozemans@azvu.nl
J J
JJ
Hoozemans
R
R
Veerhuis
I
I
Janssen
A J
AJ
Rozemuller
P
P
Eikelenboom
D000544:Alzheimer Disease / Q000201:enzymology / Q000276:immunology*; D001921:Brain / Q000201:enzymology; D016207:Cytokines / Q000032:analysis / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis / Q000494:pharmacology*; D009447:Neuroblastoma; D009474:Neurons / Q000201:enzymology; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D007375:Interleukin-1; D011994:Recombinant Proteins; D015232:Dinoprostone