The early events that occur after treatment of the highly interferon a (IFN-a)-sensitive human lymphoblastoid Daudi cell line with human leukocyte IFN-a have been examined. IFN-a treatment ofDaudi cells results in a rapid and transient increase in the cellular content of diacylglycerol, which occurs in the absence of inositol phospholipid turnover, or an increase in intracellular calcium concentration. Furthermore, IFN-a treatment results in a selective, time-dependent activation of the Ca2+-independent E isoform of protein kinase C (PKC), while the a isoform is unaffected by IFN-a treatment. In contrast, IFN-a treatment of an IFN-resistant subclone of Daudi cells had no effect on the diacylglycerol content of cells and on the activation of PKC-e. The selective PKC inhibitor staurosporine blocked the transcriptional activation of IFN-a-stimulated genes, the cytoplasmic accumulation of mRNAs for these genes, and the induction of antiviral activity by IFN-a against vesicular stomatitis virus in IFN-sensitive cells. These observations suggest that transmembrane signaling of IFN-a involves diacylglycerol production and activation of PKC-E in Daudi cells.-,411, and -y) and Ca2+-independent (PKC-8, -E, -s, and -ti) enzymes. Furthermore, PKC-E has been shown to have Ca2+-independent phorbol ester binding activities and exhibits substrate specificity distinct from other characterized PKC isoforms (10, 11).We have investigated the early events that occur upon treatment of human Daudi lymphoblastoid cells with IFN-a in order to identify the biochemical pathways of transmembrane signaling. IFN-a treatment of these cell lines results in cessation of cell growth, protection against viral infection, and the rapid transcriptional activation of ISGs (12, 13). We report that the outstanding features of the signal transduction pathway of IFN-a in Daudi cells are the generation of DAG in the absence of inositol phospholipid turnover or Ca2+ elevation and the activation of the calcium-independent E isoform of PKC. Furthermore, staurosporine, a potent inhibitor of PKC activity blocks the transcriptional activation of ISGs, the cytoplasmic accumulation of ISG mRNA, and the induction of antiviral activity against vesicular stomatitis virus (VSV) in Daudi cells by IFN-a.
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