STAUROSPORINE INHIBITS INTERFERON ALPHA-INDUCED GENE-EXPRESSION IN FRIEND-ERYTHROLEUKEMIA CELLS THROUGH A PKC INDEPENDENT PATHWAY

Interferons (IFNs) are able to induce an increased transcription of se veral genes, which can occur within minutes of the binding of IFNs to their receptors. The specific induced transcription is mediated by the interaction of specific transcription factors with regulatory DNA seq uences that lie upstream the promoters of IFN induced genes. Phosphory lation of IFN-specific transcription factors is required for activatio n of transcription. We have studied the antiviral effect and the induc tion of gene expression by IFN-alpha in Friend Leukemia cells (FLC) in the presence of a series of inhibitors of known kinases. Protein kina se C (PKC)-specific inhibitors, i.e. calphostin C and bisindolylmaleim ide, failed to influence the IFN-induced gene expression and the antiv iral state. Likewise, little or no effect was found using inhibitors s uch as H7 or K252a. Chronic exposure of FLC to phorbol ester, that cau ses down regulation of PKC (the effectiveness of TPA treatment was pro ven by PKC enzymatic assay), has no effect on IFN-alpha action. In add ition, treatment of FLC with staurosporine prevented the induction of IFN-stimulated genes and the establishment of the antiviral state only when this drug was used at high dosage (500 nM). This result indicate s that, also in FLC activation of PKC is not involved in the transcrip tional response of the cells to IFN-alpha treatment. The non receptor tyrosine kinases of the JAK family that take part in the IFNs-specific transduction pathways could be the target of the staurosporine specif ic inhibition of the IFN-alpha action.