Potential link between interleukin-6 and arachidonic acid metabolism in Alzheimer's disease

Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interl eukin-6 (IL-6), have been implicated in the etiopathology of various inflam matory and degenerative disorders, including Alzheimer's disease (AD). Prev iously, we detected the presence of IL-6 in cortices of AD patients. On the other hand, non-steroidal antiinflammatory drugs (NSAIDs), potent inhibito rs of prostaglandin synthesis, have been shown to be beneficial in the trea tment of AD. Until now, it remained unclear whether and how these two obser vations were functionally connected. Here, we show that PGs are able to ind uce IL-6 synthesis in a human astrocytoma cell line. PGE, and PGE,, but not PGD(2) and PGF(2 alpha), led to a rapid and transient induction of astrocy tic IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE(2) pote ntiated IL-1 beta-induced IL-6 mRNA synthesis. These results suggest a poss ible link between the release of PGs from activated microglia and the astro cytic synthesis of IL-6, which itself may affect neuronal cells, as hypothe sized for Alzheimer's disease. Finally we demonstrate that microglia are a strong source of PGE(2) synthesis indicating that these cells may act as th e origin of the pathogenic cascade.