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A family of cytokine-inducible inhibitors of signalling

Abstract

Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation1. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of theSTAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters1,2,3,4. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS (ref. 5) form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.

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Figure 1: Phenotype of IL-6 unresponsive M1 cell clone, 4A2.
Figure 2: Comparison of the amino-acid sequences of SOCS-1, SOCS-2, SOCS-3 and CIS.
Figure 3: Expression of SOCS-1 suppresses IL-6-induced macrophage differentiation of M1 cells.
Figure 4: Expression of mRNA for SOCS family members in vitro and in vivo.
Figure 5: SOCS-1 suppresses the phosphorylation and activation of gp130 and Stat-3.

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Acknowledgements

We thank R. Simpson and R. Moritz for recombinant mouse IL-6, C. McFarlane for help with production of recombinant cytokines, S. Cory for the pPGKpuropA vector, P. Lock for the pPGKneo vector and U. Novak for her generous advice regarding electrophoretic mobility shift assays. B.Roberts, D. Cary, L. Di Rago, S. Mifsud and N. Sprigg are thanked for their excellent technical assistance. D.J.H. was supported by a Queen Elizabeth II Postdoctoral Fellowship from the Australian Research Council. T.J.G. is a senior research fellow of the NH & MRC. This work was supported by the Anti-Cancer Council of Victoria, Melbourne, Australia, AMRAD Operations Pty Ltd, Melbourne, Australia, The National Health and Medical Research Council, Canberra, Australia, The J.D. and L. Harris Trust, the National Institutes of Health, Bethesda, Maryland and the Australian Federal Government Cooperative Research Centres Programme.

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Correspondence to Douglas J. Hilton.

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Starr, R., Willson, T., Viney, E. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997). https://doi.org/10.1038/43206

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