Regulation of the release of interleukin-6 from human astrocytoma cells.
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 microM), 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 EC50 values of 4.5 microM, 8 nM, and 4.5 pM, respectively. The respective effects of histamine, SP, and IL-1 beta 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 phosphatidylinositol 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-1 beta, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Cadman
E D
ED
Pharmaceutical Products Division, Abbott Laboratories, Chicago, Illinois 60064.
Witte
D G
DG
Lee
C M
CM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000503:physiopathology; D001254:Astrocytoma / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D007700:Kinetics; D011493:Protein Kinase C / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D005904:Glial Fibrillary Acidic Protein; D007295:Inositol Phosphates; D007375:Interleukin-1; D015850:Interleukin-6; D013373:Substance P; D006632:Histamine; D003513:Cycloheximide; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D007213:Indomethacin