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SOCS3 regulates the plasticity of gp130 signaling

Nature Immunology volume 4, pages 546–550 (2003)Cite this article

Abstract

Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway. SOCS3 is upregulated by several signals in macrophages and has been implicated as a regulator of various signaling pathways. Here we show that phosphorylation of STAT3 is prolonged in mouse Socs3-deficient macrophages after stimulation with interleukin-6 (IL-6) but not IL-10, indicating that SOCS3 specifically affects signaling mediated by IL-6 and gp130. IL-6 induces a wider transcriptional response in Socs3-deficient macrophages than in wild-type cells; this response is dominated by interferon (IFN)-regulated genes owing to an excess of STAT1 phosphorylation. Thus, SOCS3 functions to control the quality of the response to IL-6 and prevents the activation of an IFN-induced program of gene expression.

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Figure 1: SOCS3 deficiency increases phosphorylation of STAT3.
Figure 2: Expression of SOCS3 controls phosphorylation of STAT3 induced by IL-6.
Figure 3: IL-6 signaling in the absence of SOCS3 induces an IFN-like response.
Figure 4: Phosphorylation of SHP2 is increased in Socs3−/− macrophages.

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Acknowledgements

We thank P. Goodell for advice on fetal liver reconstitution and for suggesting the use of the CD45.1+CD45.2+ F1 mice as recipients, and D. Marshall and J. Morris for doing the microarray experiments. This work was supported by grants from the US National Institutes of Health (AI53478-01) and the American Heart Association (grant 344901) to P.J.M., by a grant from Cancer Center CORE (P30 CA 21765) and by American Lebanese Syrian Associated Charities. In the early stage of this work, R.L. was recipient of a fellowship from the Deutsche Forschungsgemeinschaft (LA 1262/1-1). R.L. and J.M. are supported by Nationales Genomforschungsnetzwerk grant 01GS0113.

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Author notes

  1. Anne-Laure Pauleau

    Present address: Centre National de la Recherche Scientifique, UMR8125, Institute Gustave Roussy, 39 rue Camille-Desmoulins, F-94805, Villejuif, France

  2. Yutaka Takahashi

    Present address: Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

Authors and Affiliations

  1. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Roland Lang, Anne-Laure Pauleau, Robert Rutschman & Peter J Murray

  2. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technical University, Munich, Germany

    Roland Lang & Jörg Mages

  3. Howard Hughes Medical Institute and Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Evan Parganas, Yutaka Takahashi & James N Ihle

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Lang, R., Pauleau, AL., Parganas, E. et al. SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 4, 546–550 (2003). https://doi.org/10.1038/ni932

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