Cross talk of the interferon-α/β signalling complex with gp130 for effective interleukin-6 signalling

Authors


  • Communicated by: Kohei Miyazono

* : E-mail: tada@m.u-tokyo.ac.jp

Abstract

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-α/β signalling complex, generated by spontaneously produced IFN-α/β, in efficient IFN-γ signalling.

Results In the present study, we have demonstrated that the IFN-α/β 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-α/β 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-α/β 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-α/β signal provides a foundation for strong cellular responses to IL-6, IFN-γ, 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.

Ancillary