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, usin g the U373 human astrocytoma cell line as a model system for astrocyte s, 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 geni stein 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 in hibitor of protein kinase C, also completely inhibited interleukin-6 p roduction, The phorbol ester 12-O-tetradecanoylphorbo 13-acetate induc ed interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation, Prol onged exposure to phorbol ester eliminated subsequent stimulation by p horbol ester but only partially decreased interleukin-1-induced interl eukin-6 and had no effect on the activities of selected inhibitors inc luding calphostin C. We conclude that tyrosine kinase activity is esse ntial for interleukin-1-induced interleukin-6 production in U373 astro cytoma cells and that activity of a phorbol ester-insensitive, atypica l protein kinase C isozyme may also be involved.