Type I interferon differential therapy for erythroleukemia: specificity of STAT activation.
Type I interferons (IFNs), pleiotropic cytokines with antiviral, antiproliferative, apoptotic, and immunoregulatory functions, are efficacious in the treatment of malignancies, viral infections, and autoimmune diseases. Binding of these cytokines to their cognate receptor leads to activation of the Jak-signal transducers and activators of transcription (STAT) signaling pathway and altered gene expression. This signal pathway has been intensely studied using human IFN-alpha 2 and IFN-beta. However, there are over 14 human IFN-alpha subtypes and over 10 murine IFN-alpha subtypes, with a single IFN-beta subtype in both species. J2E cells are immortalized at the proerythroblast stage of development and produce a rapid and fatal erythroleukemia in vivo. These cells retain the ability to respond to erythropoietin in vitro by proliferating, differentiating, and remaining viable in the absence of serum. Here, we show that J2E cells are also functionally regulated differentially by IFN subtype treatment in vitro. A novel finding was the selective activation of STAT and mitogen-activated protein kinase (MAPK) molecules by different subtypes binding the IFN receptor. These findings indicate distinct effects for individual type I IFN subtypes, which are able to differentially activate members of the STAT and MAPK family. Finally, we investigated the efficacy of IFN naked DNA therapy in treating J2E-induced erythroleukemia in athymic nude mice. IFN subtypes differentially regulated the onset of erythroleukemia with delayed onset and increased survival, possibly via a reduction in cell viability, and enhanced antiproliferative and apoptotic effects observed for IFNA6 and IFNA9 treatment, respectively. Moreover, these data highlight the necessity to choose the best IFN subtype in disease treatment.
Cull
Vanessa S
VS
Division of Veterinary and Biomedical Sciences, Western Australian Biomedical Research Institute, Murdoch University, Perth, Western Australia, Australia.
Tilbrook
Peta A
PA
Bartlett
Emmalene J
EJ
Brekalo
Natalie L
NL
James
Cassandra M
CM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D015316:Genetic Therapy; D007370:Interferon Type I / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D004915:Leukemia, Erythroblastic, Acute / Q000628:therapy*; D051379:Mice; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007370:Interferon Type I; D008894:Milk Proteins; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004247:DNA; D020928:Mitogen-Activated Protein Kinases