Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a cytokine, which plays an important role in many chronic inflammatory diseases. IL-6 belongs to a family of 10 cytokines, which all act via receptor complexes containing the cytokine receptor subunit gp130. On cells, IL-6 first binds to a specific membrane-bound IL-6R and the complex of IL-6 and IL-6R interacts with gp130 leading to signal initiation. Whereas gp130 is widely expressed throughout the body, the IL-6R is only found on some cells including hepatocytes and some leucocytes. A soluble form of the IL-6R is an agonist capable of transmitting signals through interaction with the gp130 protein. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells, which are unresponsive to IL-6 alone, as they do not express the membrane-bound IL-6R. We have named this process trans-signalling. We provided evidence that a soluble form of the IL-6 family signalling receptor subunit gp130 is the natural inhibitor of IL-6 trans-signalling responses. We showed that in chronic inflammatory diseases such as inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma as well as in colon cancer, IL-6 trans-signalling is critically involved in the maintenance of the disease state. Moreover, in all these animal models, the progression of the disease can be interrupted by specifically interfering with IL-6 trans-signalling using recombinant-soluble gp130Fc protein. The pathophysiologic mechanisms by which the IL-6/soluble IL-6R complex perpetuates the inflammatory state are discussed.
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PMID:Interleukin-6 trans-signalling in chronic inflammation and cancer. 1664 Jun 55

In murine models of Crohn's disease, rheumatoid arthritis and colon cancer, IL-6 (interleukin-6) signalling via the sIL-6R (soluble IL-6 receptor; termed IL-6 trans-signalling) has been shown to promote the pathology associated with these conditions. These detrimental activities can, however, be selectively blocked by soluble forms of the gp130 (glycoprotein 130) receptor. Although sgp130 (soluble gp130) therefore represents a viable therapeutic modality for the treatment of these conditions, the mass manufacture of such biologics is often expensive. The advent of molecular farming has, however, provided an extremely cost-effective strategy for the engineering of recombinant proteins. Here, we describe the expression and production of a biologically active sgp130 variant that is expressed in transgenic tobacco plants as an ELP (elastin-like peptide)-fusion protein (mini-gp130-ELP). Mini-gp130-ELP consists of the first three domains of gp130 (Ig-like domain and cytokine binding module) fused to 100 repeats of ELP. Expression of mini-gp130-ELP did not affect the growth rate or morphology of the transgenic plants, and purification was achieved using inverse transition cycling. This approach led to an overall yield of 141 microg of purified protein per g of fresh leaf weight. The purified mini-gp130-ELP specifically inhibited sIL-6R-mediated trans-signalling as measured by binding to the IL-6-sIL-6R complex and through its ability to block sIL-6R-mediated activation of STAT3 (signal transducer and activator of transcription 3) phosphorylation and proliferation in human hepatoma cells and murine pre-B-cells. Consequently, the present study validates the potential application of molecular farming in transgenic tobacco plants as a strategy for the expression and purification of therapeutically advantageous biologics such as sgp130.
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PMID:Functional expression of a biologically active fragment of soluble gp130 as an ELP-fusion protein in transgenic plants: purification via inverse transition cycling. 1671 47

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
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PMID:Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. 1837 60

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, including cyclin D1 and interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation, and tumorigenesis in the intestine, suggesting that activation of FXR by nonbile acid ligands may protect against intestinal carcinogenesis.
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PMID:Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. 1898 Dec 89

There is growing evidence that tumors are sustained and promoted by inflammatory signals from the surrounding microenvironment. Two papers by Grivennikov et al. and Bollrath et al. in this issue of Cancer Cell demonstrate the importance of the interleukin-6 family of proinflammatory cytokines and their downstream effector STAT3 in colitis-associated colon cancer.
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PMID:Inflammation and cancer: IL-6 and STAT3 complete the link. 1918 45

The level of interleukin-6 (IL-6) is correlated with prognosis and liver metastasis in colon cancer. However, the relationship between macrophage-derived and tumor-derived IL-6 in colon cancer remains unclear. We harvested the macrophage supernatant and studied the IL-6-inducing ability of the macrophage supernatant on the colon cancer cell line HT-29. The macrophage supernatant effectively induced IL-6 secretion of colon cancer cells in vitro. The macrophage supernatant and recombinant IL-6 neutralized with anti-IL-6 or ant-gp130 antibodies dramatically decreased the IL-6-induction ability of cancer cells. IL-6-induction occurred through phosphorylation of STAT3. We analyzed the surgical specimens of 126 patients with colon cancer using an immunohistochemical staining method and demonstrated the colocalization of macrophages and the expression of IL-6 in colon cancer patients. These results indicate that macrophages in tumor infiltrates could release IL-6, which in turn conditions colon cancer cells, causing them to secrete IL-6 themselves via phosphorylation of STAT3.
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PMID:Interleukin-6 (IL-6) released by macrophages induces IL-6 secretion in the human colon cancer HT-29 cell line. 1927 24

The complex pathogenesis of inflammatory bowel disease (IBD) and inflammation induced colon cancer involves a wide range of mediators including cytokines. Recent investigations underline the fundamental role of interleukin-6 (IL-6) signaling in the development and maintenance of IBD and for the progression of this inflammation to colon cancer. The molecular mechanisms of this pathway, the source of the cytokine and the identity of target cells in the intestine are incompletely understood. It is known that the circulating and intestinal levels of IL-6 as well as the soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. Remarkably, mucosal T cells of IBD patients are extremely resistant to apoptosis and a large fraction of these cells express membrane-bound gp130 but not the IL-6R. Increasing evidence suggests that the development and perpetuation of IBD relies on IL-6 synthesized by T-cells and myeloid cells and on increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T-cells, a process called IL-6 trans-signaling. Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells. Here we review these pro- and anti-inflammatory properties of IL-6 in IBD and inflammation induced colon cancer and we will summarize the consequences of these new results for the prospects of IL-6 targeted therapeutic strategies for the treatment of chronic inflammatory diseases such as IBD.
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PMID:Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease. 1951 47

Interleukin-6 (IL-6) has been implicated in tumorigenesis; however, its role is still far from being clearly defined. Regulation of IL-6 expression is highly complex, and additional complexity is introduced by single-nucleotide polymorphisms in the IL-6 gene. These single-nucleotide polymorphisms might influence mRNA transcription, which might in turn result in increased susceptibility to certain tumors. The aim of this study was to analyze IL-6 mRNA and protein expressions in sporadic colon cancer. Influence of IL-6-174 G/C polymorphism on IL-6 mRNA expression and sporadic colon cancer susceptibility was evaluated as well. The frequency of IL-6-174 G/C was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. IL-6 mRNA and protein expressions were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. No statistically significant difference in IL-6 mRNA expression in tumor tissue compared with the corresponding normal tissue was observed (p = 0.116). No correlation was found between IL-6 mRNA and protein expressions and clinicopathological features of sporadic colon tumors. There was no association of IL-6-174 G/C genotypes with IL-6 mRNA expression in colon tumors and corresponding normal mucous tissue (p = 0.355; p = 0.152). Finally, there was no association of IL-6-174 G/C with susceptibility to sporadic colon cancer.
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PMID:Interleukin-6-174 G/C polymorphism is not associated with IL-6 expression and susceptibility to sporadic colon cancer. 2013 36

In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.
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PMID:Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. 2035 76

A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor alpha(M)beta(2) binding motif (Fibgamma(390-396A)), revealed that alpha(M)beta(2)-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibgamma(390-396A) mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibgamma(390-396A) mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-alpha(M)beta(2) interactions may be useful in preventing and/or treating this important subset of malignancies.
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PMID:Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. 2023 70


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