NSAIDS INHIBIT THE IL-1-BETA-INDUCED IL-6 RELEASE FROM HUMAN POSTMORTEM ASTROCYTES - THE INVOLVEMENT OF PROSTAGLANDIN E-2

Epidemiological studies have shown that steroidal as well as non-stero idal 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 th e mechanisms responsible are still unknown. In this study we investiga ted at cellular level the influence of two anti-inflammatory drugs-dex amethasone and indomethacin-and an experimental specific cyclooxygenas e-2 inhibitor, BF389, on the production of the pro-inflammatory cytoki ne IL-6 and the inflammatory mediator PGE(2) by human astrocytes. Two human past-mortem astrocyte cultures (A157 and A295) and astroglioma c ell lines (U251 and U373 MG) were found to secrete considerable amount s of IL-6 upon stimulation with IL-1 beta. The glucocorticoid dexameth asone inhibited the IL-1 beta-activated release of IL-6 from the postm ortem astrocyte cultures A157 and A295 and from the astroglioma cell l ines; The non-specific cyclooxygenase inhibitor indomethacin and BF389 only suppressed the IL-6 release by post-mortem astrocyte culture A15 7. This post-mortem astrocyte culture was found to produce large amoun ts of PGE(2) upon stimulation with IL-1 beta whereas in the supernatan ts of the postmortem astrocyte culture A295 and the astroglioma cell l ines, low PGE(2) concentrations were detected. Addition of exogenous P GE(2) prevented the inhibitory effect of indomethacin and BF389 on thr IL-1 beta-activated IL-6 release from A157 astrocytes and largely pot entiated the IL-1-induced release of IL-6 from all astrocytes/astrogli oma cells tested. Dexamethasone also inhibited the PGE(2) release from the astrocytes and astroglioma cells, however the inhibitory effect o f dexamethasone on the IL-1 beta-activated IL-6 release could not be p revented by the addition of PGE(2). The observed reduction of IL-6 and /or PGE(2) from astrocytes may be involved in the mechanism underlying the beneficial effects of these drugs in AD. (C) 1997 Elsevier Scienc e B.V.