Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling.
BACKGROUND
Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-alpha/beta signalling complex, generated by spontaneously produced IFN-alpha/beta, in efficient IFN-gamma signalling.


RESULTS
In the present study, we have demonstrated that the IFN-alpha/beta signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-alpha/beta signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-alpha/beta stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity.


CONCLUSIONS
The constitutive weak IFN-alpha/beta signal provides a foundation for strong cellular responses to IL-6, IFN-gamma, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a 'receptosome'-like structure, allowing the unique signalling cross talks to occur.
Mitani
Y
Y
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Takaoka
A
A
Kim
S H
SH
Kato
Y
Y
Yokochi
T
T
Tanaka
N
N
Taniguchi
T
T
D000818:Animals; D002478:Cells, Cultured; D058966:Contactins; D019281:Dimerization; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000276:immunology / Q000502:physiology; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020239:Receptor Cross-Talk; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D058966:Contactins; D007370:Interferon Type I; D016898:Interferon-alpha; D008565:Membrane Proteins; D019006:Neural Cell Adhesion Molecules; D017471:Receptors, Interferon; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D019000:Phosphotyrosine; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases