Gastroenterology

Gastroenterology

Volume 123, Issue 6, December 2002, Pages 2064-2081
Gastroenterology

Special Reports and Reviews
Suppressors of cytokine signaling: Relevance to gastrointestinal function and disease,☆☆,

https://doi.org/10.1053/gast.2002.37068Get rights and content

Abstract

Background & Aims: The suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2 domain-containing proteins. Currently, there are 8 members of the SOCS family, of which a number have been implicated strongly in the negative regulation of cytokine signal transduction pathways. Methods: This review focuses on recent discoveries about 4 SOCS family members, SOCS-1, -2, and -3, and cytokine-inducible SH2-domain containing (CIS), and provides more limited information about other SOCS family members. Results: A large number of cytokines and growth factors are now known to induce SOCS proteins. In turn, SOCS inhibit the actions of a growing number of cytokines and growth factors in vitro or in vivo. SOCS proteins exert their inhibitory effects at the level of activation of janus kinases (JAKs) or by competing with transcription factors for binding sites on activated cytokine receptors. SOCS proteins also may mediate the ubiquitination and subsequent degradation of the SOCS protein and its bound signaling complex. Genetic modification of SOCS genes in mice has revealed crucial roles in the negative regulation of a number of important physiologic parameters including interferon γ activity, growth, blood cell production, and placental development. Conclusions: Information about SOCS action in gastrointestinal function and disease is only just emerging, but available data indicate a role in growth of gastrointestinal tissues, inflammatory bowel disease, and cancer.

GASTROENTEROLOGY 2002;123:2064-2081

Section snippets

Discovery

The first member of the SOCS family of proteins to be discovered was called cytokine-inducible SH2-domain containing (CIS) protein. CIS was found in a screen for negative regulators of IL-3 and EPO signaling.20 Subsequent investigations using a number of methods detected a different but homologous protein called SOCS-1. SOCS-1 was discovered based on its ability to inhibit IL-6–mediated differentiation of the myeloid leukemia M1 cells into macrophages.21 SOCS-1 also was detected in a yeast

Suppressors of cytokine signaling 1

SOCS-1 mRNA is induced by and inhibits a variety of cytokines, including IFNs, IL-4, IL-6, LIF, and EPO in vitro or in vivo (Table 1). Cytokine induction of SOCS-1 mRNA generally is rapid and transient, with detectable induction within 15 minutes, peak induction at 2 hours, and reversion to baseline by 4 hours. SOCS-1 inhibits cytokine action by inhibiting JAK activation in vitro or in vivo. The SH2 domain of SOCS-1 is thought to be a key mediator of JAK inhibition because it binds to the

Suppressors of cytokine signaling 2

Compared with SOCS-1, fewer cytokines induce SOCS-2 and these include GH and prolactin (Table 1). On cytokine exposure in vivo or in vitro, initial low levels of SOCS-2 expression climb steadily over a period of 8 hours or longer,35, 78 which contrasts with the rapid, more transient mRNA induction observed for SOCS-1 and other SOCS such as SOCS-3. Initial studies examined whether SOCS-2, like SOCS-1, modulates cytokine action in M1 cells. SOCS-2 overexpression caused only a partial inhibition

Suppressors of cytokine signaling 3

After SOCS-1, SOCS-3 is the most extensively studied member of the SOCS family. SOCS-3 shares several features in common with SOCS-1. This includes a high degree of amino acid homology and induction by a wide range of cytokines including IL-2, IL-3, IL-4, IL-6, IL-10, GH, leptin, prolactin, LIF, EPO, thrombopoietin, IFN-γ, tumor necrosis factor α, and insulin. Similar to SOCS-1, SOCS-3 inhibits the actions of multiple cytokines (Table 1) and is rapidly but transiently induced by cytokines. In

Cytokine inducible SH2-domain containing proteins

CIS was discovered in a search for immediate-early cytokine-responsive genes20 and shares the highest sequence and structural homology with SOCS-2. CIS is induced in response to many hematopoietic cytokines such as IL-1, IL-6, IL-12, IL-13, LIF, G-colony stimulating factor, thrombopoietin, IL-2, IL-3, EPO, but also a number of nonhematopoietic cytokines such as GH, leptin, and prolactin (Table 1). The mRNA induction pattern of CIS is rapid and transient as for SOCS-1 and SOCS-3, except there

Conclusions and future implications

Numerous in vitro experiments have highlighted the diverse role that CIS, SOCS-1, -2, and -3 proteins may play in the negative regulation of cytokine signaling. Information is beginning to emerge about SOCS-4, -5, -6, and -7. The generation of genetically modified mice has validated and assigned a number of the SOCS members as key mediators of important physiologic processes (Table 2).

. Summary of genetic modification studies of SOCS genes and their implications for function

ProteinPhenotypeEmpty Cell

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    Address requests for reprints to: P. Kay Lund, M.D., University of North Carolina at Chapel Hill, School of Medicine, Medical Sciences Research Building, Room 252, Chapel Hill, North Carolina 27599-7545. e-mail: [email protected].

    ☆☆

    Supported by the Anti-Cancer Council of Victoria, Melbourne, Australia; the National Health and Medical Research Council, Canberra, Australia; The National Institute of Health, Bethesda, MD (grant CA-22556 to D.J.H.; DK40247, DK47769, CA44684, and P30-DK-34987 to P.K.L.; CA72319 predoctoral training grant supporting M.E.M.); and the Australian Federal Government Cooperative Research Centres Program.

    Drs. Greenhalgh and Miller contributed equally to this work.

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