Suppressor of cytokine signaling-2: A growth hormone-inducible inhibitor of intestinal epithelial cell proliferation

doi:10.1053/j.gastro.2004.05.016

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 570-581

https://doi.org/10.1053/j.gastro.2004.05.016 Get rights and content

Abstract

$Background & Aims :$ Growth hormone (GH) and insulin-like growth factor-I (IGF-I) increase intestinal growth. GH is thought to act indirectly via IGF-I. In several models, including rats given total parenteral nutrition (TPN), IGF-I more potently stimulates mucosal growth than GH, even when GH induces similar circulating IGF-I levels. These studies test the hypothesis that GH induces a suppressor of cytokine signaling (SOCS), which inhibits intestinal epithelial cell (IEC) proliferation. Methods: Rats on TPN received vehicle, GH, or IGF-I. Jejunal SOCS (SOCS-1, -2, -3, and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I messenger RNA (mRNA) were quantified. Caco-2, IEC-6 cells, and SOCS-2 null and wild-type (WT) mice were used to examine the expression and functional role of SOCS-2. $Results :$ As reported previously, IGF-I, but not GH, prevented mucosal atrophy during TPN, although GH elevated plasma IGF-I and increased body weight. GH, but not IGF-I, induced jejunal SOCS-2 mRNA. SOCS-2 mRNA levels in GH and IGF-I-treated rats inversely correlated with mucosal weight. SOCS-2 is expressed in Caco-2 cells, and elevated SOCS-2 expression in postconfluent cells is associated with reduced proliferative rates. SOCS-2 overexpression in Caco-2 cells inhibited cell proliferation and promoted differentiation. In IEC-6 cells, GH induced SOCS-2 and reduced basal or IGF-I-induced proliferation. GH also reduced proliferative activity in isolated crypts from WT but not SOCS-2 null mice, and SOCS-2 null crypts showed enhanced proliferative responses to GH and IGF-I. SOCS-2 null mice have increased intestinal weight and length. $Conclusions :$ SOCS-2 is a GH-inducible, novel inhibitor of intestinal epithelial cell proliferation and intestinal growth.

Section snippets

Rat TPN model

A rat TPN model was used to compare the effects of GH and IGF-I on jejunal SOCS expression and to test whether these effects correlate with effects on mucosal growth. The TPN model permits comparisons of GH and IGF-I action under conditions of identical nutrient intake.4 TPN experiments were performed at the University of Wisconsin-Madison and approved by the Institutional Animal Care and Use Committee and have been described in detail elsewhere.19 Briefly, 250-g male Sprague Dawley rats

Effects of GH and IGF-I in TPN-fed rats

Body weight, plasma IGF-I, and mucosal mass data for some of the treatment groups have been reported previously for the animals used in this study.19 These prior data are shown in Table 1 to show key points relevant to the new analyses, which tested for correlations between mass of jejunal mucosa and jejunal SOCS-2 mRNA. As reported previously in these animals19 and previous studies with similar experimental design,4, 5 TPN-fed rats showed reductions in body weight gain, plasma IGF-I, and mass

Discussion

Although trophic actions of GH on the intestine have been noted in animal models of chronic GH excess2 or with GH treatment of GH-deficient animals,35, 36 GH does not prevent or reverse the atrophy of the intestinal mucosa associated with restriction of oral nutrient and TPN in rats.4 This is despite the fact that GH treatment increases circulating IGF-I and causes similar increases in body weight as observed with IGF-I treatment, which does potently stimulate mucosal growth and crypt cell

Acknowledgements

The authors thank Dr. Christopher Greenhalgh for providing the SOCS-2 null mice and for valuable discussion.

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Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway
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Citation Excerpt :
Recent studies have shown that the STAT3/SOCS3 pathway regulates the signal transduction of many factors related to insulin sensitivity and glucose metabolism [10,11]. SOCS2, as an inhibitor of growth hormone (GH) actions, is an important regulator of hepatic triglyceride (TG) metabolism in the development of NAFLD [12,13]. SOCS2-deficient mice are protected from high-fat-diet (HFD)-induced steatosis with impaired glucose intolerance [12].
Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced hepatic steatosis with impaired glucose tolerance in mice. However, the underlying mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fasted C57BL/6 J mice or db/db mice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment. Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling pathway in db/db mice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis. The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis. The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part, by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression. SOCS2 may represent a new therapeutic target for the treatment of diabetes.
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GH inmunoreactivity was found in colonic mucosa [45]. GH increases intestinal growth by inducing IGF-1 expression [61,62]. Large cell neuroendocrine carcinoma (LCNEC) of the colon and rectum was immunoreactive for GH and GHR, suggesting that overproduction of GH and GHR may participate in the development of colorectal tumors [63,64].
The gene for pituitary growth hormone (GH-N) in man belongs to a multigene locus located at chromosome 17q24.2, which also harbors four additional genes: one for a placental variant of GH-N (named GH-V) and three of chorionic somatommamotropin (CSH) type. Their tandem arrangement from 5′ to 3′ is: GH-N, CSH-L, CSH-1, GH-V and CSH-2. GH-N is mainly expressed in the pituitary from birth throughout life, while the remaining genes are expressed in the placenta of pregnant women. Pituitary somatotrophs secrete GH into the bloodstream to act at receptor sites in most tissues. GH participates in the regulation of several complex physiological processes, including growth and metabolism. Recently, the presence of GH has been described in several extrapituitary sites, such as neural, ocular, reproductive, immune, cardiovascular, muscular, dermal and skeletal tissues. It has been proposed that GH has an autocrine action in these tissues. While the body of evidence for its presence is constantly growing, research of its possible function and implications lag behind. In this review we highlight the evidence of extrapituitary synthesis of GH in humans.
Insulin-Like Growth Factors in the Gastrointestinal Tract and Liver
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In animal models and in human studies of short bowel syndrome, intestinal atrophy, or inflammatory bowel disease, IGF-1 is more potent in stimulating intestinal growth than GH. This may be because of induction of suppressor of cytokine signaling 2 by GH but not IGF-1.88 More recently the role of GLP-2 in this respect has been examined.
Growth Factors in the Gastrointestinal Tract
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Growth Factors in the Gastrointestinal Tract
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Suppressor of cytokine signaling-2 gene disruption promotes Apc <sup>Min/+</sup> tumorigenesis and activator protein-1 activation
2010, American Journal of Pathology
Epigenetic in vitro and in vivo studies suggest that suppressor of cytokine signaling-2 (SOCS2) may normally limit tumorigenesis in the intestine; however, this theory has not been directly tested. We hypothesized that SOCS2 deficiency promotes spontaneous intestinal tumorigenesis in Apc^Min/+ mice. Therefore, we quantified tumor number, size, and load in the small intestine and colon using SOCS2^+/+/Apc^Min/+, SOCS2^+/−/Apc^Min/+, and SOCS2^−/−/Apc^Min/+ mice and assayed hematocrit as an indirect marker of disease severity. Biochemical and histological assays were used to assess mechanisms. Heterozygous and homozygous disruption of SOCS2 alleles promoted 166 and 441% increases in tumor load in the small intestine, respectively, accelerated development of colon tumors, and caused severe anemia. SOCS2 deletion promoted significant increases in intestinal insulin-like growth factor-I mRNA but did not affect plasma insulin-like growth factor-I. Western blots and immunohistochemical analysis demonstrated that tumor and nontumor intestinal tissue of SOCS2^−/−/Apc^Min/+ mice had increased serine 727 phosphorylation of signal transducer and activator of transcription 3 compared with SOCS2^+/+/Apc^Min/+ mice. Moreover, electromobility shift assays showed that SOCS2 deletion did not alter signal transducer and activator of transcription 3 DNA binding. However, tumors and small intestine from SOCS2^−/−/Apc^Min/+ showed dramatic increases in activator protein-1 (AP-1) DNA binding, and SOCS2 overexpression in vitro reduced levels of AP-1. These studies indicate that SOCS2 deletion promotes the spontaneous development of intestinal tumors driven by mutations in the adenomatous polyposis coli/β-catenin pathway and activates AP-1. Therefore, reduced expression or epigenetic silencing of SOCS2 may serve as a useful biomarker for colorectal cancer risk.

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^☆: Supported by an NCI predoctoral training grant 5 T32 CA72319 (to M.E.M.), National Institutes of Health Grants DK-40247 (to P.K.L.) and DK-42835 (to D.M.N.), and funds from the college of Agricultural and Life Sciences, University of Wisconsin-Madison, and facilitated by the molecular histopathology core of the Center for Gastrointestinal Biology and Disease (P30-DK-34987) and the DNA synthesis core of the Lineberger Cancer Center (CA 16086).

¹: M.E.M. and C.Z.M. contributed equally to this work.

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Basic-alimentary tractSuppressor of cytokine signaling-2: A growth hormone-inducible inhibitor of intestinal epithelial cell proliferation☆

Abstract

Section snippets

Rat TPN model

Effects of GH and IGF-I in TPN-fed rats

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Nutr

J Nutr

J Biol Chem

Gastroenterology

Gastroenterology

Gene

Gastroenterology

J Surg Res

Clin Nur

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Trends Mol Med

J Gastrointest Surg

Genomics

IGFs and the digestive tract

GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally fed rats

Am J Physiol

Enterotrophic effect of insulin-like growth factor-I but not growth hormone and localized expression of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and -5 mRNAs in jejunum of parenterally fed rats

JPEN J Parenter Enteral Nutr

Growth hormone did not enhance mucosal hyperplasia after small-bowel resection

Scand J Gastroenterol

Expression of insulin-like growth factor-II and insulin-like growth factor binding proteins during Caco-2 cell proliferation and differentiation

J Cell Physiol

Small bowel adaptation with growth hormone and glutamine after massive resection of rat’s small bowel

Nutr Hosp

Basic-alimentary tract
Suppressor of cytokine signaling-2: A growth hormone-inducible inhibitor of intestinal epithelial cell proliferation☆