Mutational switch of an IL-6 response to an interferon-γ-like response

^*Cancer Research United Kingdom London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom; and ^‡School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom

Communicated by George R. Stark, Cleveland Clinic Foundation, Cleveland, OH (received for review February 27, 2002)

Abstract

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-γ receptors are, however, completely different. Remarkably, it is shown here that, in mouse embryo fibroblasts lacking STAT3, IL-6 mediates an IFN-γ-like response including prolonged activation of STAT1, the induction of multiple IFN-γ-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-γ-like response. The data encourage the view that the very disparate IFN-γ 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.

Footnotes

↵ † A.P.C.-P., S.T., and B.S. contributed equally to this work.
↵ § Present address: Institute of Animal Breeding and Genetics, Veterinaerplatz 1, A-1210 Vienna, Austria.
↵ ¶ Present address: Gene Expression Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico Spallanzani, 00149 Rome, Italy.
↵ ‖ Present address: University of Essen, Gastroenterology and Hepatology, Hufelandstrasse 55, 45122 Essen, Germany.
↵ ** To whom reprint requests should be addressed. E-mail: ian.kerr{at}cancer.org.uk.
↵ ‡‡ Present address: DiPartimento di Genetica, Biologia e Biochimica, via Santena 5bis, 10126 Torino, Italy.
Abbreviations:

JAK,

Janus kinase;

STAT,

signal transducer and activator of transcription;

IFNGR1,

-2, interferon-γ receptor subunit 1, 2;

MEF,

mouse embryo fibroblast