Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009324 (ulcerative colitis)
 17,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10-deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.
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PMID:IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. 1667 Jul 70

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue-damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.
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PMID:Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication. 1700 11

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
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PMID:A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. 1713 88

Inflammatory bowel disease (IBD), typified by Crohn's disease and ulcerative colitis, is a common disorder characterized by recurrent and serious inflammation of the gastrointestinal tract. Recent immunologic advances have established that T cells and inflammatory cytokines play a pivotal role in the gastrointestinal inflammation of IBD. However, many cytokines not only elicit inflammation but also protect host against microbial invasion. Hence, suppression of these dual-purpose cytokines often exposes the patients to significant risk of infection. Recent research on Interleukin (IL)-23, IL-17, and IL-17 producing T cells has become the vanguard of further understanding the contribution of cytokines to autoimmune and inflammatory diseases. IL-23 is a newly discovered member of the IL-12-related cytokine family, and is primarily involved in the differentiation of pathogenic T cells characterized by their production of IL-17. IL-17 is a potent inflammatory mediator implicated in a number of autoimmune diseases. The discovery of this IL-23/IL-17-mediated inflammatory axis is having a profound impact on the elucidation of T cell-mediated pathogenesis as well as development of novel therapeutic targets. In this review, we discuss the current literature and present our recent studies on the role of IL-23 and IL-17 in the pathogenesis of IBD. Controlling the expression/production of IL-23 and IL-17 is an approach that would allow the development of a novel treatment strategy with more anti-inflammatory efficacy and potentially with less suppressive effects on host defenses.
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PMID:After interleukin-12p40, are interleukin-23 and interleukin-17 the next therapeutic targets for inflammatory bowel disease? 1732 63

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) occurring in the gut of genetically susceptible individuals independent of a specific pathogen. The interaction between antigen-presenting cells and the local bacterial flora contributes to an uncontrolled activation of mucosal CD4+ T lymphocytes with the consecutive release of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, IL-23, IL-27, and also IL-17, which is attributed to a specific, differentiated CD4+ lineage called Th17 (TH-IL17, THi). Recent data suggest that IL-6 contributes to Th17 differentiation. However, to clarify the importance of Th17 cells in IBD further data are needed. So far, CD has been attributed to a Th1-mediated disease, whereas UC exhibits a modified Th2 cytokine response. In both diseases CD4+ T cells at the site of inflammation are critically dependent on antiapoptotic IL-6 signaling. Thereby, IL-6 induces the transcription factor STAT-3 via transsignaling (activation of a cell lacking membrane-bound IL-6 receptor via soluble IL-6 receptor). STAT-3 itself induces the antiapoptotic factors bcl-2 and bcl-xL, thus resulting in T-cell resistance against apoptosis. This vicious circle of T-cell accumulation, mediated by apoptosis resistance, finally leading to chronic inflammation, can be blocked by anti-IL-6 receptor antibodies. This review highlights the role of IL-6 in IBD immunopathogenesis and its clinical relevance in IBD therapy and diagnostics.
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PMID:Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. 1747 78

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases with unsolved pathogenesis. Imbalanced Th1/Th2 may play a role in the sustained inflammation of IBD. In China, CD is rare but the incidence of UC has been rising steadily in the last two decades. We investigated the expression of IL-12 (p40) and IFN-gamma, and the activational state of Stat4 signaling in mucosal tissues at the site of disease from 30 active UC patients in comparison with 30 healthy controls. RT-PCR analyses revealed increased mRNA expression of IL-12 (p40) but not IFN-gamma in UC patients. Western blot analyses discovered, for the first time, increased levels of constitutive Stat4 in the cytoplasm and phosphorylated Stat4 in the nucleus of mucosal cells from UC patients. We conclude that a heightened, perhaps persistent, activational state of IL-12/Stat4, and/or IL-23/Stat4 signaling may be present in active Chinese UC patients, and possibly involved in chronic inflammation in UC.
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PMID:Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. 1804 21

Colorectal cancer represents a life-threatening complication of inflammatory bowel diseases. Statistics indicate that the risk to develop colorectal cancer is higher in patients affected by ulcerative colitis and to a lesser extent by Crohn's disease and that such a risk is directly proportional to the number of years of active disease. These observations suggest that chronic inflammation may substantially contribute to cancer development. However the molecular mechanisms underlying this process have been only recently started to be clarified. Indeed from the initial concept that the release of free radicals during inflammation might induce the accumulation of genetic mutations thus leading to the onset of dysplastic cells, it is now becoming clear that the large amount of cytokines and growth factors released during inflammation by immune and non immune cells may influence the carcinogenesis process. IL-6 and IL-23, cytokines which play key roles in the induction and maintenance of gut inflammation during IBDs, have been recently shown to influence the development and growth of colitis associated colorectal cancer. Moreover, the activation of the nuclear factor kappa B (NF kappa B), a transcription factor activated by several cytokines released during inflammation and responsible for many of their proinflammatory effects, have been shown to promote the growth of the colon tumors in experimental models.
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PMID:Cytokines: from gut inflammation to colorectal cancer. 1847 65

Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
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PMID:Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. 1849 80

A patient from the University of North Carolina Hospitals is presented who developed Crohn's disease of the ileal J-pouch following restorative proctocolectomy for ulcerative colitis. Inflammation of the ileal pouch in human inflammatory bowel disease (IBD) represents the best clinical example of the importance of host-enteric microbial interactions, and this case highlights rapid advances in our understanding of the role of the enteric microbiota in the immunopathogenesis of IBD, impacting on clinical care. Successful management of this patient necessitated accurate diagnosis as there are several inflammatory and non-inflammatory conditions of the pouch that present with similar symptoms. Diagnostic measures included serologic assays of response to microbial antigens, including ASCA, anti-OmpC, anti-Cbir1, and pANCA with DNAse sensitivity. Although the serologic detection of selective loss of tolerance to microbial antigens defines clinically important subgroups of inflammatory bowel disease patients, the clinical value of these serodiagnostic tests is a matter of debate. Genome wide screens have also identified NOD2/CARD15, IL23 receptor, and ATG16L1 variants as important in IBD susceptibility and pathogenesis. These genetic associations have also provided new insights into the importance of interaction between the host and microbes in the pathogenesis of IBD, but the precise mechanisms by which these gene variants contribute to disease development remain to be determined. Genetic associations and serological markers will ultimately be used to define important clinical subgroups of disease, predict natural history, and ultimately identify patient populations for early therapeutic intervention.
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PMID:Abnormal mucosal immune response to altered bacterial flora following restorative proctocolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations. 2123 20

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.
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PMID:The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. 1871 Sep 29


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