Interferonα activates NF-κB in JAK1-deficient cells through a TYK2-dependent pathway

Abstract

In addition to activating members of the STAT transcription factor family, interferon α/β (IFNα/β) activates the NF-κB transcription factor. To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-κB activation by IFN, we examined NF-κB activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH), IFN activates STAT1, STAT2, and STAT3, as well as NF-κB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells, IFN induces NF-κB activation and NF-κB 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-κB activation by IFN. Moreover, IFN does not promote NF-κB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-κB signaling pathway. In the IFN signaling pathway leading to STAT activation, both JAK1 and TYK2 are essential, whereas NF-κB activation requires only TYK2. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.