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

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