REGULATION OF THE RELEASE OF INTERLEUKIN-6 FROM HUMAN ASTROCYTOMA-CELLS

Recent evidence suggests that the level of interleukin-6 (IL-6) is ele vated in Alzheimer's disease (AD) brains. IL-6 is produced by reactive glial cells and could potentially affect neuronal survival. Understan ding the biochemical mechanism that regulates the production and relea se of IL-6 by astrocytic cells may help to identify potential targets for therapeutic intervention in AD. in the present study, glial fibril lary acidic protein-positive human U373MG astrocytoma cells were used as a model of reactive astrocytes. Production of IL-6 in response to d rug treatment was monitored with an ELISA assay. Histamine (1-100 mu M ), substance P (SP; 1-100 nM), and human interleukin-1 beta (IL-1 beta ; 1-30 pM) stimulated the release of IL-6 in a time- and concentration -dependent manner, with EC(50) values of 4.5 mu M 8 nM and 4.5 pM, res pectively. The respective effects of histamine, SP, and IL-1 beta were effectively blocked by the histamine H-1, SP, and IL-1 receptor antag onists, supporting a receptor-mediated event for these agents. Both hi stamine and SP enhanced the formation of inositol phosphates and incre ase intracellular calcium levels, suggesting that the phosphatidylinos itol bisphosphate/protein kinase C pathway may be involved in the IL-6 release process. Indeed, phorbol 12-myristate 13-acetate, a protein k inase C activator, also evoked IL-6 release from the U373MG cells. On the other hand, IL-1 beta, which produces a much more robust release o f IL-6 than histamine or SP, has no effect on inositol phosphate forma tion or intracellular calcium levels. The biochemical mechanism of the release of IL-6 in response to IL-1 beta remains to be elucidated.