title: Evidence that MAP (mitogen-activated protein) kinase activation may be a necessary but not sufficient signal for a restricted subset of responses in IL-1-treated epidermoid cells.
abstract: We have investigated the activation of mitogen-activated protein kinase (MAP-kinase) in KB human epidermoid carcinoma cells treated with interleukin 1 (IL-1). MAP-kinase activity was transient; the time required for activity to reach a maximal level was dependent upon the dose of IL-1, ranging from 15 minutes to 45 minutes. The level of kinase induction correlated well with dose-response curves for two characteristic IL-1-induced responses, PGE2 and IL-6 production. MAP-kinase activity returned to basal levels within 2 hours regardless of the amount of IL-1 added to the system. Exposure of KB cells to free IL-1 was accordingly restricted to periods of 2 hours or less, by replacing IL-1 with an excess of IL-1 receptor antagonist. Even after 2 hours exposure, the ability of IL-1 to induce IL-6 or PGE2 was still IL-1ra-inhibitable by more than 80%, suggesting that events downstream of, or parallel to MAP-kinase activation, requiring the continual formation of new IL-1 receptor complexes, are needed to fully elicit these responses. Two general serine/threonine kinase inhibitors, K252a and quercetin, were found to strongly inhibit MAP kinase in vivo with ED50s of c. 100 nM and 30 microM, respectively. At these concentrations, both compounds effectively inhibited IL-1-driven PGE2 and IL-6 induction without affecting general protein synthesis or secretion. Other non-selective kinase inhibitors had less effect on MAP-kinase activation or IL-1-induced biological responses. The transient activation of MAP-kinase induction correlated strikingly with activation of the transcription factor NF-kappa B. IL-1-induced NF-kappa B activation was, however, relatively insensitive to inhibition by K252a or quercetin. We suggest that MAP-kinase is likely to be a necessary, but not sufficient, intermediate in some (IL-6, PGE2 induction) but not all (NF-kappa B activation) IL-1 responses in these cells.
authors.affiliation: Department of Biochemistry, Immunex Research and Development Corporation, Seattle, WA 98101.
authors.forename: T A
authors.initials: TA
authors.lastname: Bird
authors.forename: H D
authors.initials: HD
authors.lastname: Schule
authors.forename: P B
authors.initials: PB
authors.lastname: Delaney
authors.forename: J E
authors.initials: JE
authors.lastname: Sims
authors.forename: B
authors.initials: B
authors.lastname: Thoma
authors.forename: S K
authors.initials: SK
authors.lastname: Dower
mesh_terms: D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000235:genetics; D015342:DNA Probes; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D015342:DNA Probes; D026121:Indole Alkaloids; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D004247:DNA; C049985:staurosporine aglycone; D011794:Quercetin; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015232:Dinoprostone