Special Reports and ReviewsSuppressors of cytokine signaling: Relevance to gastrointestinal function and disease☆,☆☆,★
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).Protein Phenotype Empty Cell
References (165)
- et al.
Interleukin-10-deficient mice develop chronic enterocolitis
Cell
(1993) - et al.
Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells
Immunity
(1994) - et al.
The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T-cell receptor alpha mutant mice
Gastroenterology
(1999) - et al.
CD4+ T-cell population mediates development of inflammatory bowel disease in T-cell receptor alpha chain-deficient mice
Gastroenterology
(1997) - et al.
Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone
Gastroenterology
(1993) - et al.
Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone
Gastroenterology
(2001) - et al.
Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice
Am J Pathol
(1998) - et al.
Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling
Semin Immunol
(2000) - et al.
Cloning and characterization of novel CIS family genes
Biochem Biophys Res Commun
(1997) - et al.
Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3
Biochem Biophys Res Commun
(1997)
Suppressor of cytokine signaling-1 inhibits VAV function through protein degradation
J Biol Chem
Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells
Blood
The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2
J Biol Chem
SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine
Cell
Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo
J Biol Chem
SOCS3 is essential in the regulation of fetal liver erythropoiesis
Cell
Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1
Immunity
Developmental defects of lymphoid cells in Jak3 kinase-deficient mice
Immunity
SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality
Cell
Inflammatory bowel disease: etiology and pathogenesis
Gastroenterology
SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo
Immunity
Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 signaling
FEBS Lett
Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling
J Biol Chem
SOCS-1, -2, -3: selective targets and functions downstream of the prolactin receptor
Mol Cell Endocrinol
Inactivation of SSI-1, a JAK/STAT inhibitor, in human hepatocellular carcinomas, as revealed by two-dimensional electrophoresis
J Hepatol
Dampened SOCS: an altered balance between STAT activating and SOCS inhibitory signals regulate interferon-gamma expression in LPMC
Gastoenterology
Regulation of SOCS-1 expression by translational repression
J Biol Chem
Evidence for translational repression of the SOCS-1 major open reading frame by an upstream open reading frame
Biochem Biophys Res Commun
Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling
J Biol Chem
Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism
Blood
Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation
J Biol Chem
SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms
J Biol Chem
Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction
FEBS Lett
Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone
J Biol Chem
Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor
J Biol Chem
Enhanced growth of small bowel in transgenic mice that overexpress human insulin-like growth factor I
Gastroenterology
Lack of Socs2 expression causes the high-growth phenotype in mice
Genomics
CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells
J Exp Med
Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice
Nat Genet
Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice
J Exp Med
Cytokine imbalance and autoantibody production in T cell receptor-alpha mutant mice with inflammatory bowel disease
J Exp Med
Metallothionein-human GH fusion genes stimulate growth of mice
Science
Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice
Endocrinology
IgG1 plasmacytosis in interleukin 6 transgenic mice
Proc Natl Acad Sci U S A
Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation
J Clin Invest
CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling
Nature
Specific inhibition of Stat3 signal transduction by PIAS3
Science
Inhibition of Stat1-mediated gene activation by PIAS1
Proc Natl Acad Sci U S A
A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors
EMBO J
A family of cytokine-inducible inhibitors of signalling
Nature
Cited by (0)
- ☆
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.