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  • Review Article
  • Published:

SOCS proteins, cytokine signalling and immune regulation

Nature Reviews Immunology volume 7, pages 454–465 (2007)Cite this article

Key Points

  • Suppressor of cytokine signalling (SOCS) proteins are inhibitors of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways. SOCS1 also inhibits Toll-like receptor (TLR) signalling.

  • SOCS3 determines the different responses induced by the inflammatory cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10.

  • In dendritic cells (DCs), SOCS1 negatively regulates T helper 1 (TH1)-cell induction by DCs, whereas SOCS3 regulates the balance between TH2 and TH3 cells.

  • SOCS1 induced by microbes is an important mediator for interferon (IFN)-resistance.

  • In T cells, SOCS1 is important for proper positive and negative selection and CD8+ T-cell lineage determination because of the restriction of cytokine signalling during T-cell maturation.

  • SOCS1 and SOCS3 regulate TH-cell differentiation, including TH1, TH2, TH17 and TH3 cells.

  • SOCS1 and SOCS3 expression levels correlate with human allergy and inflammatory diseases including inflammation-associated tumours.

  • Overexpression or knockdown of SOCS proteins are therapeutic strategies for the treatment of autoimmune diseases and allergy and for the induction of antitumour immunity.

Abstract

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function.

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Figure 1: The structure and function of SOCS proteins.
Figure 2: Cross-talk between SOCS and the NF-κB pathways.
Figure 3: Role of SOCS proteins in T-cell development and T helper (TH)-cell regulation.
Figure 4: Role of SOCS1 and SOCS3 in inflammation-associated tumorigenesis.

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Acknowledgements

We thank Y. Nishi for preparing the manuscript. This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan.

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Authors and Affiliations

  1. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan

    Akihiko Yoshimura

  2. Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8, Saito-Asagi, Ibaraki, 567-0085, Osaka, Japan

    Tetsuji Naka

  3. Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, 230–0045, Kanagawa, Japan

    Masato Kubo

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  1. Akihiko Yoshimura
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Correspondence to Akihiko Yoshimura.

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Glossary

SRC homology 2 (SH2) domain

A protein domain that is commonly found in signal-transduction molecules. It interacts specifically with phosphotyrosine-containing peptides.

Lipoxins

Leukocyte-derived eicosanoids generated during the inflammatory response that act as downregulatory signals.

Endotoxic shock

A serious systemic disorder that leads to multiple organ failure and death. It is caused by an excessive release of lipopolysaccharide (also known as endotoxin) during Gram-negative bacterial infection.

Inflammatory bowel diseases

(IBDs). Inflammatory diseases of the colon are most commonly classified as ulcerative colitis and Crohn's disease, which are believed to be T helper 1 (TH1)-type diseases. However, interleukin-23 (IL-23) and TH17 cells have recently been shown to be involved in IBDs.

Small interfering RNA

(siRNA). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference (RNAi), a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Cardiomyopathy

The chronic form of myocarditis, which is an inflammatory disease of the heart that can be induced by various microbial and viral infections. A considerable part of the pathology seems to be a direct result of dysregulated activities of T helper 1 cells and CD8+ cytotoxic T lymphocytes.

Regulatory T cells

(TReg cells). A rare population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (FOXP3) and have suppressive regulatory activity towards other T cells that are stimulated through their T-cell receptor. An absence of regulatory T cells or their dysfunction is associated with severe autoimmunity.

T helper 3 cells

(TH3 cells). A regulatory T-cell subset that was originally thought to be involved in oral tolerance, and that primarily secretes transforming growth factor-β (TGFβ). TGF-β produced by TH3 cells provides help for IgA class switching and has suppressive properties for both TH1 and TH2 cells. As the expression of CD25 and forkhead box P3 (FOXP3) is induced in T cells under experimental TH3-cell differentiation conditions (T-cell-receptor stimulation in the presence of interleukin-4 (IL-4), IL-10 and TGFβ), TH3 cells should be referred to as inducible regulatory T cells that expand in the periphery.

Nucleophosmin/anaplastic lymphoma kinase oncoprotein

(NPM/ALK oncoprotein). Oncogenic fusion tyrosine kinase which is associated with a specific type of non-Hodgkin's lymphoma. The chromosomal translocation between chromosome 5 and chromosome 2 results in fusion of the amino-terminal part of the ubiquitous nuclear protein NPM to the cytoplasmic fragment of the receptor tyrosine kinase ALK, creating a hybrid tyrosine kinase with constitutive activity.

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Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7, 454–465 (2007). https://doi.org/10.1038/nri2093

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