Recent evidence suggests that the level of interleukin‐6 (IL‐6) is elevated in Alzheimer's disease (AD) brains. IL‐6 is produced by reactive glial cells and could potentially affect neuronal survival. Understanding the biochemical mechanism that regulates the production and release of IL‐6 by astrocytic cells may help to identify potential targets for therapeutic intervention in AD. In the present study, glial fibrillary acidic protein‐positive human U373MG astrocytoma cells were used as a model of reactive astrocytes. Production of IL‐6 in response to drug treatment was monitored with an ELISA assay. Histamine (1–100 µM), substance P (SP; 1–100 nM), and human interleukin‐1β (IL‐1β; 1–30 pM) stimulated the release of IL‐6 in a time‐ and concentration‐dependent manner, with EC50 values of 4.5 µM, 8 nM, and 4.5 pM, respectively. The respective effects of histamine, SP, and IL‐1β were effectively blocked by the histamine H1, SP, and IL‐1 receptor antagonists, supporting a receptor‐mediated event for these agents. Both histamine and SP enhanced the formation of inositol phosphates and increase intracellular calcium levels, suggesting that the phosphatidyl‐inositol bisphosphate/protein kinase C pathway may be involved in the IL‐6 release process. Indeed, phorbol 12‐myristate 13‐acetate, a protein kinase C activator, also evoked IL‐6 release from the U373MG cells. On the other hand, IL‐1β, which produces a much more robust release of IL‐6 than histamine or SP, has no effect on inositol phosphate formation or intracellular calcium levels. The biochemical mechanism of the release of IL‐6 in response to IL‐1β remains to be elucidated.

No abstract

No abstract