Tyrosine kinase activity is essential for interleukin-1 beta--stimulated production of interleukin-6 in U373 human astrocytoma cells.
We have investigated the roles of tyrosine kinase and protein kinase C activity in interleukin-1 beta-induced interleukin-6 production, using the U373 human astrocytoma cell line as a model system for astrocytes. Compounds known to inhibit tyrosine kinases were tested for effects on interleukin-6 production in U373 cells stimulated with interleukin-1 beta. Complete to nearly complete inhibition of interleukin-1 beta-induced interleukin-6 production was observed with the flavonoids genistein and quercetin, the bisindole alkaloids staurosporine and K-252a, or the tyrphostin AG879. Herbimycin A was a potent inhibitor but did not induce complete inhibition at saturating dose. Calphostin C, an inhibitor of protein kinase C, also completely inhibited interleukin-6 production. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate induced interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation. Prolonged exposure to phorbol ester eliminated subsequent stimulation by phorbol ester but only partially decreased interleukin-1-induced interleukin-6 and had no effect on the activities of selected inhibitors including calphostin C. We conclude that tyrosine kinase activity is essential for interleukin-1-induced interleukin-6 production in U373 astrocytoma cells and that activity of a phorbol ester-insensitive, atypical protein kinase C isozyme may also be involved.
Carlson
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Hoechst Roussel Pharmaceuticals Inc., Neuroscience TD, Somerville, New Jersey, USA.
Aschmies
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D001253:Astrocytes / Q000378:metabolism*; D001254:Astrocytoma / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D015850:Interleukin-6; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate