title: Interferon alpha activates NF-kappaB in JAK1-deficient cells through a TYK2-dependent pathway.
abstract: In addition to activating members of the STAT transcription factor family, interferon alpha/beta (IFNalpha/beta) activates the NF-kappaB transcription factor. To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-kappaB activation by IFN, we examined NF-kappaB activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH), IFN activates STAT1, STAT2, and STAT3, as well as NF-kappaB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells, IFN induces NF-kappaB activation and NF-kappaB dependent gene transcription but does not activate these STAT proteins and has no effect on STAT-dependent gene transcription. Expression of a catalytically inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-kappaB activation by IFN. Moreover, IFN does not promote NF-kappaB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-kappaB signaling pathway. In the IFN signaling pathway leading to STAT activation, both JAK1 and TYK2 are essential, whereas NF-kappaB activation requires only TYK2.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and the University of Tennessee Cancer Institute, Memphis, Tennessee 38163, USA.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.forename: Aruna
authors.initials: A
authors.lastname: Murti
authors.forename: William J
authors.initials: WJ
authors.lastname: Valentine
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Du
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005354:Fibrosarcoma; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D053613:Janus Kinase 1; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D016328:NF-kappa B; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D017346:Protein Serine-Threonine Kinases