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)

Crohn's disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract characterized by chronic relapsing inflammation and catabolism. Growth hormone/insulin-like growth factor-I axis is important in inflammatory bowel disease, because of the effects on epithelial cell kinetics, collagen deposition and immunomodulation. The potential of growth hormone as a therapeutic option in inflammatory bowel disease has been proven in various clinical settings. Acquired growth hormone resistance in inflammatory bowel disease seems to be mediated by a combination of undernutrition and active inflammation. In particular, proinflammatory cytokines, such as TNF-a and interleukin-6, have been implicated as potential mediators of growth hormone resistance. The introduction of anti-TNF-alpha monoclonal antibodies has proven very efficacious in patients with inflammatory bowel disease. By reducing cytokines levels in inflammatory cells of intestinal mucosa, infliximab could interfere with cytokine-induced growth hormone resistance. Recent in vivo data have shown that acquired growth hormone resistance in patients with inflammatory bowel disease may be reversed after the administration of anti-TNF-alpha therapy.
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PMID:Growth hormone in inflammatory bowel disease. 1649 5

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

The exact pathological background of inflammatory bowel disease has not been clarified yet. Many aspects of genetical and environmental factors, as well as certain alterations of the functions of epithelial cells and immunoregulation which may attenuate chronic inflammation in the gastrointestinal tract are known. These three components have many connecting points. Among the inflammatory bowel disease genes we know only the function of the NOD2/CARD gene, and we have some idea about the OCTN and DRG genes. The function of the intestinal epithelial cells is changed in inflammatory bowel disease. The latter two genes may have a role in the increased permeability, so as the tumor necrosis factor alpha, interferon gamma may play affect it. The interleukin-10 helps the mucosal integrity. The interleukin-6 production is elevated in these diseases, and the interleukin-8 level can be elevated in case of mutation of toll like receptor 5. The tumor necrosis factor alpha, interferon gamma and lymphotoxin-3-alpha increased the chemokine secretion and adhesion molecule expression also. The amount of certain cytokines are changed in inflammatory bowel disease. There were no association between the incidence and phenotype of Crohn's disease and cytokine gene polymorphisms, except the interleukin 6 gene. It seems that these alterations are secondary, and don't play a major role in the pathogenesis of inflammatory bowel disease.
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PMID:[Molecular biology background of inflammatory bowel disease]. 1697 77

Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's disease in animals and has been hypothesized to be associated with Crohn's disease in humans. Recently, M. avium subsp. paratuberculosis isolates recovered from Crohn's disease patients were shown to have limited diversity, implying the existence of human disease-associated genotypes and strain sharing with animals (A. H. Ghadiali et al., J. Clin. Microbiol. 42:5345-5348, 2004). To explore whether these genotypic differences or similarities among human and animal isolates translated to functionally significant attributes such as variance in host preference and/or difference in magnitude of infections, we performed a global scale analysis of M. avium subsp. paratuberculosis isolates that were representative of different genotypes and host species using DNA microarrays. Genome-wide characterization of the transcriptional changes was carried out using a human monocytic cell line (THP-1 cells) in response to different genotypes of M. avium subsp. paratuberculosis isolates recovered from various hosts. We identified several differentially expressed genes during early intracellular infection, including those involved in common canonical pathways such as NF-kappaB, interleukin-6 (IL-6), mitogen-activated protein kinase/extracellular signal-regulated kinase, and Jun N-terminal protein kinase signaling, as well as genes involved in T helper type 1 (Th1) responses (such as CCL5 ligand) and those that encode several proinflammatory cytokines and chemokine receptors. The cattle and human isolates of M. avium subsp. paratuberculosis, regardless of their short sequence repeat (SSR) genotype, induced similar global gene expression patterns in THP-1 cells. They differentially regulated genes necessary for cell survival without causing major alterations in proinflammatory genes. In contrast, the sheep isolates representing diverse SSR genotypes closely resembled the global gene expression pattern of an M. avium subsp. avium isolate, and they significantly up-regulated proinflammatory genes related to IL-6, T-cell receptor, B-cell receptor, and death receptor signaling within THP-1 cells. Additionally, we demonstrated consistency among infecting genotypes of M. avium subsp. paratuberculosis isolated from diverse hosts [cattle (n=2), human (n=3), sheep (n=2), and bison (n=1)] in quantitative reverse transcription-PCR analysis of seven differentially expressed genes. While the levels of expression induced by the bison isolate were different compared with cattle or human isolates, they followed the common anti-inflammatory, antiapoptotic trend. Our data suggest that the macrophage responses to M. avium subsp. paratuberculosis isolates from cattle and human sources, regardless of genotype, follow a common theme of anti-inflammatory responses, an attribute likely associated with successful infection and persistence. However, these expression patterns differ significantly from those in THP-1 cells infected with sheep isolates of M. avium subsp. paratuberculosis or the M. avium subsp. avium isolate. These data provide a transcriptional basis for a variety of pathophysiological changes observed during early stages of infection by different strains of M. avium subsp. paratuberculosis, a first step in understanding trait-allele association in this economically important disease.
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PMID:Comparative transcriptional analysis of human macrophages exposed to animal and human isolates of Mycobacterium avium subspecies paratuberculosis with diverse genotypes. 1705 86

In the treatment of rheumatic diseases such as rheumatoid arthritis (RA) or systemic onset juvenile idiopathic arthritis (soJIA), new therapies targeting pro-inflammatory cytokines have been developed. IL-6 is a pleiotropic cytokine with a wide range of biological activities including a pro-inflammatory mediator activity. Overproduction of IL-6 has been reported to be pathologically involved in the rheumatic diseases and, therefore, blockade of IL-6 actions may improve the disease. Tocilizumab, a humanized monoclonal antibody against human interleukin-6 receptor (IL-6R), inhibits IL-6 binding to IL-6R and specifically interferes with IL-6 actions. Castleman's disease is an atypical lymphoproliferative disorder caused by the overproduction of IL-6. Tocilizumab therapy improves immunological and hematological abnormalities as well as systemic inflammatory symptoms including wasting. This translational study also confirmed the pathological significance of IL-6 in the disease. RA is a representative autoimmune inflammatory disease characterized by bone and cartilage destruction in multiple joints. Since IL-6 also plays pathological roles in RA, tocilizumab therapy has been introduced to the patients with refractory disease and has shown a strong therapeutic effect. Besides Castleman's disease and RA, tocilizumab has been shown to be effective for patients with soJIA and Crohn's disease. Tocilizumab treatment is generally well tolerated and safe. Therefore, tocilizumab can be a promising therapeutic agent for the rheumatic diseases in which IL-6 overproduction is pathologically involved.
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PMID:Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. 1721 83

This study assessed the presence of endothelial dysfunction in patients with inflammatory bowel diseases (IBDs) and evaluated the possible role of tumor necrosis factor (TNF)-alpha in the pathophysiology of this abnormality. Similar elevations in circulating markers of inflammation (C-reactive protein and interleukin-6) were observed in Crohn's disease and ulcerative colitis compared to controls. Endothelium-dependent vasodilation to acetylcholine was impaired in Crohn's disease, but not in ulcerative colitis. Endothelium-independent vasodilation to sodium nitroprusside, by contrast, was not different among the three groups. The TNF-alpha neutralizing antibody, infliximab, enhanced the responsiveness to acetylcholine, but not to nitroprusside, in Crohn's disease, without modifying vascular responses to both drugs in ulcerative colitis. In conclusion, despite comparable degrees of systemic inflammation in the two IBDs, endothelial dysfunction is a selective feature of Crohn's disease and is beneficially affected by intravascular TNF-alpha neutralization. These findings underscore the role of selective cytokine targeting in improving endothelial function in patients with Crohn's disease.
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PMID:Tumor necrosis factor-alpha antagonism improves endothelial dysfunction in patients with Crohn's disease. 1750 24

The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Crohn's disease (CD) is not well elucidated. Twenty healthy volunteers and 94 consecutive patients with CD (44 in relapse and 50 in remission) were studied. Plasma IL-6 concentrations in patients with active disease [80 +/- 9 pg/ml; mean +/- standard error of the mean (SEM)] were significantly higher than in patients with inactive disease (50 +/- 4 pg/ml; P < 0.001) or controls (3 +/- 1 pg/ml; P < 0.001). However, concentrations did not vary with the severity of CD attacks. Plasma concentrations of soluble interleukin-6 receptor (sIL-6R) in active-CD patients (77 +/- 5 ng/ml) did not differ significantly from those with inactive disease (82 +/- 5 ng/ml), while both groups had significantly raised concentrations compared with those of controls (58 +/- 6 ng/ml; P < 0.03 and P < 0.01, respectively). Plasma IL-6 concentrations correlated significantly with serum C-reactive protein (CRP) (r = 0.34; P < 0.001), whereas plasma sIL-6R concentrations did not. Taken together, these data suggest that, although IL6 and sIL6-R are both involved in the inflammatory process of CD, they are poor markers of disease activity.
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PMID:Serum interleukin-6, soluble interleukin-6 receptor and Crohn's disease activity. 1754 33

The accurate detection and quantitation of cytokines in serum are important in the study of disease mechanisms, pathogenesis, and treatment. Serum cytokines can reflect processes that are occurring at the cellular or tissue level and thus provide a means of indirectly monitoring these processes. Multiplex detection of cytokines allows the simultaneous measurement of multiple cytokines in a sample, increasing the efficiency of measuring the cytokines while reducing the serum sample volumes required for the testing. Two commercially available multiplex platforms were evaluated (Pierce SearchLight and Meso Scale Discovery), using multiplexes capable of simultaneously detecting eight cytokines. The cytokines analyzed in this study were gamma interferon, vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-6 (IL-6), macrophage inflammatory protein 1beta, monocyte chemoattractant protein 1, IL-12p40, and IL-4. The range of quantitation of the platforms, the recovery of spiked cytokines, and the detection of the cytokines in serum samples from subjects with ulcerative colitis, Crohn's disease, rheumatoid arthritis, and psoriasis were examined. The findings showed that the detection of the cytokines was highly dependent upon the platform, with the consistency of the detection of cytokines across platforms being dependent upon the cytokine being analyzed. A careful examination of platform assay performance must be made prior to utilizing multiplex platforms in a study. While some cytokines will give similar patterns of results across platforms, others will be highly variable. The use of the same platform within a study or across studies where data will be compared is advised.
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PMID:Simultaneous detection of eight analytes in human serum by two commercially available platforms for multiplex cytokine analysis. 1800 17

Chronic inflammation, as seen in conditions such as rheumatoid arthritis and Crohn disease, is in part driven by discordant production of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 (IL-6). Tyrosine kinase activity is essential to lipopolysaccharide-induced cytokine production in monocytes, and previous studies by us and others have implicated a role for the Tec kinase Bruton's tyrosine kinase (Btk) in inflammatory cytokine production. Here we show that knockdown of Btk using RNA interference results in decreased tumor necrosis factor-alpha, but not IL-6 production. Further investigations into the signaling mechanisms regulating IL-6 production led to the discovery that the Tec kinase bone marrow tyrosine kinase gene in chromosome X (Bmx) regulates Toll-like receptor-induced IL-6 production. Our data further showed that Bmx-dependent super-induction of IL-6 does not involve nuclear factor-kappaB activity. More detailed investigations of pathways downstream of Bmx signaling revealed that Bmx targets the IL-6 3' untranslated region to increase mRNA stabilization via a novel, thus far undefined, p38 mitogen activated protein kinase-independent pathway. These data have important implications for the design of therapeutics targeted against specific cytokines and their regulators in inflammatory disease.
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PMID:Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFkapp}B activity. 1802 55

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune responses and inflammatory reactions. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) and, therefore, an agent blocking IL-6 actions can be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit glycoprotein (gp) 130. This family also includes IL-11, oncostatin-M, and leukemia inhibitory factor (LIF). In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of gp130. Tocilizumab is a humanized antihuman IL-6 receptor antibody designed using genetic engineering technology. Tocilizumab recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 actions. Tocilizumab is expected to ameliorate the autoimmune inflammatory diseases with IL-6 overproduction and has been clinically developed as a therapeutic agent for RA, systemic-onset and articular types of JIA, Crohn's disease, etc. Tocilizumab has been shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of RA. Immunopharmacology and clinical benefit of tocilizumab in RA is addressed.
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PMID:Humanized antihuman IL-6 receptor antibody, tocilizumab. 1807 45


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