SOCS3 in immune regulation of inflammatory bowel disease and inflammatory bowel disease-related cancer

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
Cytokine & growth factor reviews (Impact Factor: 5.36). 05/2012; 23(3):127-38. DOI: 10.1016/j.cytogfr.2012.04.005
Source: PubMed


Inflammatory bowel disease (IBD) has unclear pathogenesis and it is related to the increasing risk of developing colorectal cancer (CRC). Recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6. The major transcription factors including STAT3 have been shown to play a major role in transmitting inflammatory cytokine signals to the nucleus. The suppressors of cytokine signaling (SOCS) 3 protein is the key physiological regulators of cytokine-mediated STAT3 signaling. As such it influences the development of inflammatory and malignant disorders like this associated with IBD. Here we review the complex function of SOCS3 in innate and adaptive immunity, different cell types (macrophages, neutrophils, dendritic cells, B cells, T cells and intestinal epithelial cells) and the role of SOCS3 on the pathogenesis of inflammatory bowel disease (IBD) and IBD-related cancer. Finally, we explore how this knowledge may open novel avenues for the rational treatment of IBD and IBD-related cancer.

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    • "SOCS3 inhibits the production of IL-2, a cytokine crucial for the activation of T cells, effectively inhibiting initial T cell activation. The over-expression of SOCS3 in this setting might therefore be the result of an effort to limit the activation of T helper cells in the inflamed mucosa, while the increased expression of STAT3 might be the result of SOCS3-independent activation via IL10[51], [52]. It is also possible that the SOCS3 expression detected stems from cells other than the lymphocytes, as both neutrophils, macrophages and epithelial cells have been shown to express SOCS3 in IBD mucosa[53]. "
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    ABSTRACT: In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn's disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns. Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores. Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls. There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "The dietary feeding of crocin significantly suppressed several inflammatory events and NF-κB expression in the colorectal mucosa of the mice that received DSS. Inflammatory genes, such as COX2, iNOS, TNF-α, and IL-1β, are the most common target genes participating in the activation of NF-κB and are associated with a number of chronic inflammatory diseases, including IBD and IBD-related colorectal carcinogenesis [37, 38, 45, 46, 62]. In the current study, we observed decreases in the mRNA expression levels of NF-κB, COX-2, iNOS, TNF-α, IL-1β, and IL-6 in the mice treated with DSS and crocin when compared to the mice given DSS alone. "
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    ABSTRACT: A natural carotenoid crocin is contained in saffron and gardenia flowers (crocuses and gardenias) and is used as a food colorant. This study reports the potential inhibitory effects of crocin against inflammation-associated mouse colon carcinogenesis and chemically induced colitis in male ICR mice. In the first experiment, dietary crocin significantly inhibited the development of colonic adenocarcinomas induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) in mice by week 18. Crocin feeding also suppressed the proliferation and immunohistochemical expression of nuclear factor- (NF-) κB but increased the NF-E2-related factor 2 (Nrf2) expression, in adenocarcinoma cells. In the second experiment, dietary feeding with crocin for 4 weeks was able to inhibit DSS-induced colitis and decrease the mRNA expression of tumor necrosis factor α, interleukin- (IL-) 1β, IL-6, interferon γ, NF-κB, cyclooxygenase-2, and inducible nitric oxide synthase in the colorectal mucosa and increased the Nrf2 mRNA expression. Our results suggest that dietary crocin suppresses chemically induced colitis and colitis-related colon carcinogenesis in mice, at least partly by inhibiting inflammation and the mRNA expression of certain proinflammatory cytokines and inducible inflammatory enzymes. Therefore, crocin is a candidate for the prevention of colitis and inflammation-associated colon carcinogenesis.
    Full-text · Article · Dec 2012 · Evidence-based Complementary and Alternative Medicine
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    ABSTRACT: Our understanding of how axon regeneration is controlled in both the peripheral and central nervous systems remains fragmentary. Research into the regenerative capacity of adult neurons has elucidated PTEN and SOCS3 as distinctive but complementary arms of the regenerative program. These molecules act as negative regulators of major signaling pathways and impact the processes occurring in the cell body, such as protein translation and transcription, and in the axons, such as cytoskeleton assembly. In this review, we summarize the role of PTEN and SOCS3 in limiting axon regeneration and discuss the molecular and cellular mechanisms underlying their growth-inhibitory effects.
    No preview · Article · Dec 2012 · International Review of Neurobiology
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