Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An imbalance of immunoregulatory factors is believed to contribute to uncontrolled mucosal Th1 cell activation in Crohn's disease (CD). IL-18, a macrophage-like cell-derived cytokine, is involved in Th1 clone development, and IFN-gamma production. Therefore, IL-18 expression was investigated in CD. Whole mucosal intestinal tissue and lamina propria mononuclear cells (LPMC) of 12 CD and 9 ulcerative colitis (UC) patients and 15 non-inflammatory bowel disease (IBD) controls were tested for IL-18 by semiquantitative RT-PCR and Western blot analysis. Transcripts for IL-18 were found in all samples tested. However, increased IL-18 mRNA accumulation was detected in both mucosal and LPMC samples from CD in comparison to UC and controls. In CD, transcripts for IL-18 were more abundant in the mucosal samples taken from involved areas. An 18-kDa band consistent with mature IL-18 was predominantly found in CD mucosal samples. In mucosal samples from non-IBD controls, IL-18 was present as a 24-kDa polypeptide. Consistently, active IL-1beta-converting enzyme (ICE) subunit (p20) was expressed in samples from either CD or UC, whereas, in colonic mucosa from non-IBD controls, ICE was synthesized as precursor (p45) only. To confirm that IL-18 produced in CD tissue was functionally active, CD LPMC were treated with a specific IL-18 antisense oligonucleotide. In these cultures, IL-18 down-regulation was accompanied by a decrease in IFN-gamma expression. In aggregate, our data indicate that IL-18 up-regulation is a feature of CD and suggest that IL-18 may contribute to the local immunoinflammatory response in CD.
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PMID:Bioactive IL-18 expression is up-regulated in Crohn's disease. 1038 10

Macrophages are important in the host's immunological and inflammatory responses. There is a large population of these cells in the normal intestinal mucosa where they represent the major antigen presenting cell population capable of determining the type of T cell responses that develop to luminal antigens. Studies suggest that the normal intestinal macrophages cannot be easily induced to mediate acute inflammatory responses. In active inflammatory bowel disease there is an increase in the mucosal macrophage population, derived from circulating monocytes. These recruited macrophages are phenotypically different from the resident population of cells and play a major role in mediating the chronic mucosal inflammation seen in patients with ulcerative colitis and Crohn's disease. They secrete many cytokines that are important in the proinflammatory responses, such as interleukin (IL)-1, IL-6, IL-8, IL-12, IL-18, and tumor necrosis factor-alpha. They also release reactive metabolites of oxygen and nitrogen and proteases that degrade the extracellular matrix. Macrophages also appear to be important during resolution of inflammation and repair of the intestinal mucosa that occurs during disease remission.
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PMID:The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. 1070 Nov 46

The etiology and pathogenesis of inflammatory bowel disease remains an area under intense investigation. Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4+ T cells and macrophages in inflamed intestinal mucosa. IL-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4+ T cells by inducing interferon-gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes in human CD and murine CD model.
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PMID:Interleukin-18 and Crohn's disease. 1117 8

Although IL-18 is an inducer of IFN-gamma and Th1 responses. IL-18 is a proinflammatory cytokine by several criteria. In several animal models. antibodies that neutralize endogenous IL-18 reduce the severity of disease. Endotoxin lethality is prevented by anti-IL-18. Even in models that are interferon-y independent, neutralization of IL-18 prolongs survival. Anti-IL-18 also protects the liver against cellular injury induced by toxins or activated T cells. In models of hepatic melanoma metastasis. IL-18 blockade reduces the adherence of malignant cells by preventing IL-18 upregulation of vascular endothelial adhesion-1 molecule expression. IL-18 and IL-12 act synergistically to stimulate I cells and natural killer cells to produce IFN-gamma but neutralization of IL-18 prevents IL-12 induction of IFN-gamma. IL-18. like several cytokines. can be used to enhance host defense against tumors in mice a mechanism that is most often IFN-gamma-dependent. Nevertheless. it is the proinflammatory portfolio of IL-18 which likely contributes to enhanced host defenses. In models or arthritis, lung injury or inflammatory bowel disease, neutralization of IL-18 reveals the important role of this cytokine in mediating inflammation.
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PMID:Interleukin-18, a proinflammatory cytokine. 1120 86

Elevated expression of interleukin (IL)-18 mRNA and protein in intestinal mucosa, attributable to activated monocytes and macrophages in that site, has been reported in patients with inflammatory bowel disease (IBD). However, changes in serum IL-18 concentrations in patients with IBD have not been reported. We measured bioactive IL-18 in serum from patients with IBD, using an enzyme-linked immunosorbent assay (ELISA). Mean serum IL-18 concentrations in 5 patients with Crohn disease (CD) were 400 pg/mL, approximately 1.7 times higher than concentrations in 21 control subjects (p < 0.01). However, serum IL-18 was not increased in patients with ulcerative colitis (UC). These results suggest that like other T-helper type 1 (Th1) cytokines IL-18 may play a key pathogenetic role in Th1-mediated disorders, such as CD. Regulation and expression of IL-18 appears to differ between CD and UC, and serum IL-18 may be a useful clinical marker for CD.
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PMID:Serum interleukin-18 concentrations in patients with inflammatory bowel disease. 1204 53

An imbalance of T helper cell type 1 (Th1) versus type 2 (Th2) polarization in favor of Th1 cell subsets appears to be a key pathogenic mechanism in chronic inflammatory bowel disease (IBD), in particular in Crohn's disease. The interferon gamma-inducing factor interleukin (IL)-18 acts in strong synergism with the Th1 polarizing cytokine IL-12. Recent studies provide evidence for the participation of IL-18 in the pathogenesis of IBD: IL-18 expression is increased in inflamed lesions of Crohn's disease patients and neutralization of IL-18 in different models of experimental colitis resulted in a dramatic amelioration of disease severity. IL-18 and IL-1beta are cleaved and thereby activated by the interleukin-1beta converting enzyme (ICE). Activation of ICE also occurs during different types of infectious colitis, and ICE expression and subsequent release of IL-1beta and IL-18 significantly contribute to intestinal inflammation. ICE knockout mice as well as mice treated with the ICE inhibitor pralnacasan are protected against experimental mucosal inflammation. Thus, inhibition of ICE represents an intriguing new target that requires further investigation in animal models.
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PMID:Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation. 1210

We have previously reported that in peripheral blood mononuclear cells (PBMC), the augmented expression of the beta isoform of the human glucocorticoid receptor (hGRbeta), as a putative dominant negative regulator of glucocorticoid action, is associated with glucocorticoid (GC) unresponsiveness of UC patients. In this study, we quantified the levels and serial changes of hGR transcripts in PBMC of IBD patients by a real-time fluorescence monitoring of PCR. As results, relative hGRbeta mRNA expression was significantly higher in the active stage of UC than in inactive periods of UC or CD patients. Longitudinal analysis revealed that hGRbeta mRNA expression in UC was increased after the relapse of inflammation, suggesting that the overproduction of cytokines during inflammation may be responsible. In in vitro culture experiments of human lymphoid cell (CEM) and human PBMC, IL-7, and IL-18 increased hGRbeta mRNA expression in these cells but GC itself did not. Through these analyses, it is indicated that the inflammatory cytokines altered the splicing condition of the primary transcript of hGR gene in IBD patients.
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PMID:Quantitative analysis for human glucocorticoid receptor alpha/beta mRNA in IBD. 1220 14

Interleukin (IL)-18 is a cytokine with a broad array of effector functions, the most prominent of which is to act synergistically with IL-12 in interferon-gamma production and the induction of a strong T-helper-1-mediated immune response. In addition, IL-18 also upregulates the production of proinflammatory cytokines such as IL-1 and tumor necrosis factor-alpha. Analysis of IL-18-deficient mice revealed an important role of IL-18 in the activation of macrophages and natural killer cells in the context of infection with intracellular bacteria or parasites. In humans, it was reported that IL-18 is elevated at sites of inflammation in inflammatory bowel disease (IBD), particularly in Crohn's disease, suggesting a possible role for IL-18 in the development and persistence of IBD. In this review we summarize recent findings on the functional role of IL-18 in the pathogenesis of colitis with a special focus on murine models of IBD. The neutralizing mouse anti-mouse IL-18 antibodies generated in our group should facilitate the evaluation of the efficiency of therapeutic blockade of endogenous IL-18 in chronic mouse models of colitis besides the use of recombinant forms of the inhibitory IL-18-binding protein.
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PMID:Anti-interleukin-18 therapy in murine models of inflammatory bowel disease. 1257 21

Dentritic cells (DC) as antigen-presenting cells are most likely responsible for regulation of abnormal T cell activation in Crohn's disease (CD), a chronic inflammatory bowel disease. We have analyzed the expression of activation and maturation markers on DC in the colon mucosa from patients with CD compared with normal colon, using immunohistochemical techniques. We found two distinct populations of DC present in CD patients: a DC-specific ICAM-3 grabbing non-integrin (DC-SIGN)(+) population that was present scattered throughout the mucosa, and a CD83(+) population that was present in aggregated lymphoid nodules and as single cells in the lamina propria. In normal colon the number of DC-SIGN(+) DC was lower and CD83(+) DC were detected only in very few solitary lymphoid nodules. Co-expression of activation markers and cytokine synthesis was analyzed with three-color confocal laser scanning microscopy analysis. CD80 expression was enhanced on the majority of DC-SIGN(+) DC in CD patients, whereas only a proportion of the CD83(+) DC co-expressed CD80 in CD as well as in normal tissue. Surprisingly, IL-12 and IL-18 were only detected in DC-SIGN(+) DC and not in CD83(+) DC. A similar pattern of cytokine production was observed in normal colon albeit to a much lesser extent. The characteristics of these in-situ-differentiated DC markedly differ from the in-vitro-generated DC that simultaneously express DC-SIGN, CD83 and cytokines.
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PMID:Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn's disease. 1259 43

Throughout this symposium, recurrent themes were highlighted that may provide important clues to the pathogenesis of mucosal inflammation and IBD. First, the mucosal immune system is unique: Studies describing signaling paradigms in peripheral immunocytes should be re-explored in the gut where the rules that govern cell signaling may not be the same. Paradigms are a point of departure to characterize similarities and differences in mucosal immunity. A good example is a differential requirement for costimulation through CD2 in lamina propria T cells compared with peripheral T cells. Furthermore, a new definition of T-cell "costimulation" is beginning to emerge. Costimulatory molecules may function to overcome physical barriers by allowing cognate interactions between other molecules or by targeting signaling complexes to membrane microdomains. This concept also relates to another recurrent theme: Interactions between signaling pathways and the cytoskeleton are functionally important. Finally, we were introduced to the novel concept of metabolic parameters as a readout for signal transduction in the immune system. In the recent past, cell signaling has been viewed as a linear exercise, connecting a cell surface receptor to a series of intermediate molecules to a program of gene expression. However, signal transduction is in fact a three-dimensional exercise in cell biology. The future challenge, as pointed out in the keynote address, is to integrate reductionist models into reality and describe networks of signal transduction pathways in complex biosystems. "Threshold" responses were emphasized, with a small incremental increase or decrease in enzymatic activity leading to an on-off phenomenon referred to as a "molecular switch." In IBD, minute genetically determined differences in enzymatic activity may be critical. This point emphasizes the power of a genetic approach in IBD. Without strong genetic evidence, it is unlikely that fuctional assays will clarify the importance of small differences in enzymatic activity that may have dramatic biologic consequences. This symposium identified recently described signal transduction molecules that may be attractive therapeutic targets in IBD. Characterization of signaling molecules such as SLP-76, SLAM, SAP, and Fyb in the mucosal immune system will be an important area of future research. Ultimately, well-developed scientific hypotheses need to be tested in human beings. This paradigm was perhaps best illustrated by PPARgamma, where reductionist models and mouse experiments have recently lead to small trials suggesting proof of concept in human IBD. This meeting also emphasized a renewed interest in innate immunity in IBD and inflammation research. The role of enteric flora in initiating and perpetuating inflammation in animal models of IBD suggests at some level the importance of the innate immune response. The role of TLRs and bacterial interactions were discussed, as was NF-kappaB as the prominent transcription factor target of innate immune activation. Numerous bridges between innate and adaptive immunity were highlighted, including IL-10, IL-12, IL-18, and IFN-gamma. Their production during an innate immune response can profoundly affect functional T-cell responses in humans. In conclusion, the challenge of understanding signal transduction in IBD is one of integrating well-characterized inflammatory pathways into a complex biologic system that is inhabited by diverse cell types that communicate, and is characterized by interactions with a complex microbial environment. Making sense of this complexity is a daunting task that will require a multifactorial approach utilizing reductionist systems, mouse models, genetic studies, and ultimately human clinical trials.
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PMID:Meeting summary: Signal transduction pathways in immune and inflammatory cells. November 30-December 3, 2000, Amelia Island, Florida, U.S.A. 1265 35


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