title: Interferon-alpha inhibits proliferation of Ba/F3 cells by interfering with interleukin-3 action.
abstract: Interferons (IFNs) are potent inhibitors of cell proliferation that are used for the treatment of several haematological malignancies. The mechanisms through which IFNs exert their antiproliferative effects on target cells, however, are largely unknown. Here we show that IFN-alpha, in murine Ba/F3 cells, directly interferes with the action of the essential mitogen interleukin (IL)-3. In transiently transfected Ba/F3 cells, IFN-alpha efficiently inhibited the IL-3-stimulated expression of a luciferase reporter construct, GAS-luc, that is activated through the JAK2/STAT5 pathway. Electrophoretic mobility shift assays and Northern blot experiments, however, revealed that neither the IL-3-induced DNA binding of STAT5 nor the transcription of the STAT5-dependent genes oncostatin-M, pim-1 and c-fos were suppressed by IFN-alpha, suggesting that the diminished expression of the luciferase protein was due to a direct inhibition of IL-3-stimulated protein synthesis. This hypothesis was supported by the observation that IFN-alpha, even though it had no effect on the transcription of the c-fos gene, efficiently suppressed the IL-3-dependent expression of the c-Fos protein. Furthermore, our results indicate that IFN-alpha induced an overexpression of the double-stranded RNA-activated protein kinase (PKR), an enzyme that inhibits protein synthesis through the phosphorylation and inactivation of the eukaryotic initiation factor-2. Therefore, we hypothesize that IFN-alpha, in Ba/F3 cells, interrupts IL-3-dependent mitogenic signals, at least in part, through the suppression of protein synthesis and that induction of PKR activity may play a pivotal role in this process.
authors.affiliation: Institute of Medical Biochemistry, Medical Faculty of the University of Rostock, Germany. jaster@med.uni-rostock.de
authors.forename: R
authors.initials: R
authors.lastname: Jaster
authors.forename: E
authors.initials: E
authors.lastname: Tschirch
authors.forename: T
authors.initials: T
authors.lastname: Bittorf
authors.forename: J
authors.initials: J
authors.lastname: Brock
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D005786:Gene Expression Regulation; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008894:Milk Proteins; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007377:Interleukin-3; D008894:Milk Proteins; C508352:Osm protein, mouse; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D053683:Oncostatin M; D004247:DNA; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D019892:eIF-2 Kinase