Mutational switch of an IL-6 response to an interferon-gamma-like response.
Signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) is central to the responses to the majority of cytokines and some growth factors, including the interferons (IFNs) and the IL-6 family of cytokines. The biological responses to stimulation through the widely distributed IL-6 and IFN-gamma receptors are, however, completely different. Remarkably, it is shown here that, in mouse embryo fibroblasts lacking STAT3, IL-6 mediates an IFN-gamma-like response including prolonged activation of STAT1, the induction of multiple IFN-gamma-inducible genes, the expression of class II MHC antigens, and an antiviral state. Normal cells exposed to IL-6 thus require a STAT3-dependent function(s) to down-regulate STAT1 activity and prevent an IFN-gamma-like response. The data encourage the view that the very disparate IFN-gamma and IL-6 JAK/receptor complexes mediate a common set of generic or "core" signals which are subject to STAT3-dependent modulation to provide IL-6 specificity. The switching of one cytokine response to one closely mimicking another as a result of the loss of a single signaling component has profound implications, for example, for the interpretation of the phenotypes of knockout mice and for the clinical use of inhibitors of signaling.
Costa-Pereira
Ana P
AP
Cancer Research United Kingdom London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Tininini
Silvia
S
Strobl
Birgit
B
Alonzi
Tonino
T
Schlaak
Joerg F
JF
Is'harc
Hayaatun
H
Gesualdo
Ida
I
Newman
Sally J
SJ
Kerr
Ian M
IM
Poli
Valeria
V
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts; D005802:Genes, MHC Class II / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008285:Major Histocompatibility Complex / Q000187:drug effects; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma