NSAIDS inhibit the IL-1 beta-induced IL-6 release from human post-mortem astrocytes: the involvement of prostaglandin E2.
Epidemiological studies have shown that steroidal as well as non-steroidal anti-inflammatory drugs lower the risk of developing Alzheimer's Disease (AD). A suppressive effect of these anti-inflammatory drugs on local inflammatory events in AD brains has been suggested, however the mechanisms responsible are still unknown. In this study we investigated at cellular level the influence of two anti-inflammatory drugs-dexamethasone and indomethacin--and an experimental specific cyclooxygenase-2 inhibitor, BF389, on the production of the pro-inflammatory cytokine IL-6 and the inflammatory mediator PGE2 by human astrocytes. Two human post-mortem astrocyte cultures (A157 and A295) and astroglioma cell lines (U251 and U373 MG) were found to secrete considerable amounts of IL-6 upon stimulation with IL-1beta. The glucocorticoid dexamethasone inhibited the IL-1beta-activated release of IL-6 from the postmortem astrocyte cultures A157 and A295 and from the astroglioma cell lines. The non-specific cyclooxygenase inhibitor indomethacin and BF389 only suppressed the IL-6 release by post-mortem astrocyte culture A157. This post-mortem astrocyte culture was found to produce large amounts of PGE2 upon stimulation with IL-1beta, whereas in the supernatants of the postmortem astrocyte culture A295 and the astroglioma cell lines, low PGE2 concentrations were detected. Addition of exogenous PGE2 prevented the inhibitory effect of indomethacin and BF389 on the IL-1beta-activated IL-6 release from A157 astrocytes and largely potentiated the IL-1-induced release of IL-6 from all astrocytes/astroglioma cells tested. Dexamethasone also inhibited the PGE2 release from the astrocytes and astroglioma cells, however the inhibitory effect of dexamethasone on the IL-1beta-activated IL-6 release could not be prevented by the addition of PGE2. The observed reduction of IL-6 and/or PGE2 from astrocytes may be involved in the mechanism underlying the beneficial effects of these drugs in AD.
Blom
M A
MA
Department of Psychiatry, Academic Hospital Vrije Universiteit Amsterdam, The Netherlands. maa.blom@azvu.nl
van Twillert
M G
MG
de Vries
S C
SC
Engels
F
F
Finch
C E
CE
Veerhuis
R
R
Eikelenboom
P
P
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D001254:Astrocytoma; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D010078:Oxazines / Q000494:pharmacology; D010544:Peroxidases / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D010078:Oxazines; D010636:Phenols; C072260:Biofor 389; D003907:Dexamethasone; D010544:Peroxidases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin