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

Dysregulation of innate and adaptive intestinal immune responses to bacterial microbiota is supposed to be involved in pathogenetic mechanisms of inflammatory bowel diseases (IBDs). We investigated expression of Toll-like receptor 2 (TLR2), TLR4, and their transmembrane coreceptor CD14 in biopsy samples from patients with IBD and in non-inflamed gut mucosa from controls. Small intestine and colon samples were obtained by colonoscopy from patients with Crohn's disease (CD), ulcerative colitis (UC), and controls. Immunohistochemical analysis of cryostat sections using polyclonal and monoclonal antibodies specific for TLR2, TLR4, and CD14 showed a significant increase in TLR2 expression in the terminal ileum of patients with inactive and active UC against controls. Significant upregulation of TLR4 expression relative to controls was found in the terminal ileum and rectum of UC patients in remission and in the terminal ileum of CD patients with active disease. CD14 expression was upregulated in the terminal ileum of CD patients in remission and with active disease, in the cecum of UC patients in remission and with active disease, and in rectum of UC patients with active disease. Hence, dysregulation of TLR2, TLR4, and CD14 expression in different parts of the intestinal mucosa may be crucial in IBD pathogenesis.
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PMID:Expression of Toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. 1907 54

Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4(+)CD45Rb(high) T cells and/or CD4(+)CD45Rb(low)CD25(+) regulatory T cells were isolated and adoptively transferred to RAG1(-/-) mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [(3)H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4(+)CD45Rb(high) T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88(-/-) CD4(+) T cells showed decreased proliferation compared with WT CD4(+) T cells both in vivo and in vitro. CD4(+)CD45Rb(high) T cells from MyD88(-/-) mice did not induce wasting disease when transferred into RAG1(-/-) recipients. Lamina propria CD4(+) T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88(-/-) cells than mice receiving WT cells. In vitro, MyD88(-/-) T cells were blunted in their ability to secrete IL-17 but not IFN-gamma. Absence of MyD88 in CD4(+)CD45Rb(high) cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.
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PMID:The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease. 1820 86

The volume of research undertaken on the genetic susceptibility of inflammatory bowel disease (IBD) has been tremendous. Genome-wide linkage studies pointed towards more than 10 chromosomal regions and fine-mapping of these regions led to the identification of a number of genes, including CARD15 (NOD2), DLG5, OCTN1 and 2, TLR4 and CARD4 (NOD1). With the recent completion of the human genome project, whole genome association studies (WGAS) have now become possible and have identified additional genes (IL23R, IRGM, PTGER4, ATG16L1) for Crohn's disease and ulcerative colitis, that have subsequently been replicated. At present, the CARD15 gene is still the most understood susceptibility gene, explaining around 20% of the genetic predisposition to Crohn's disease. Prediction of disease phenotype and response to the main therapies has for many years been a dream for physicians treating IBD patients. Only now, we start to accumulate some evidence proving that genetic factors indeed influence both the clinical course of IBD patients and their likelihood of responding to certain therapies. In the coming years, we expect an exponential increase in the efforts devoted to research in this area. The optimal prediction of both disease behaviour and response to therapy might result from complex combinations of clinical, biochemical, serological and genetic factors.
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PMID:The role of genetics in inflammatory bowel disease. 1847 63

Inflammatory bowel diseases (IBD) are inflammatory diseases with a multifactorial component that involve the intestinal tract. The two relevant IBD syndromes are Crohn's disease (CD) and ulcerative colitis (UC). One factor involved in IBD development is a genetic predisposition, associated to NOD2/CARD15 and Toll-like receptor 4 (TLR4) polymorphisms that might favor infectious enterocolitis that is possibly associated to the development of IBD. The identification of specific immunologic alterations in IBD and their relationship to the etiology of the disease is a relevant research topic. The role of intra and extracellular molecules, such as transcription factors and cytokines that are involved in the inflammatory response, needs to be understood. The relevance of immunologic molecules that might drive the immune response to a T helper (Th) 1, Th 2 or the recently described Th 17 phenotype, has been demonstrated in animal models and clinical studies with IBD patients. CD and UC predominantly behave with a Th 1 and Th 2 immune phenotype, respectively. Recently, an association between CD and Th 17 has been reported. The knowledge acquired from immunologic and molecular research will help to develop accurate diagnostic methods and efficient therapies.
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PMID:[Inflammatory bowel diseases: an immunological approach]. 1857 65

Studies in adult inflammatory bowel disease (IBD) patients have highlighted associations with genetic and serologic markers and suggest an association with disease location, behaviour and natural history. Data on patients with Crohn's disease (CD, n=80), ulcerative colitis (UC, n=15) and indeterminate colitis (n=4) were collected. All individuals were analysed for CARD15 R702W, G908R and L1007fs for toll-like receptor 4 (TLR4) Asp299Gly and for anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmatic antibodies (pANCA). After a mean of 10.7 years of follow up, the disease behaviour changed in 45% of CD patients, in contrast to disease location, where only 12.5% had a change (p<0.001). The younger the age at diagnosis, the more patients presented with colonic disease (p=0.021). Also, more TLR4 Asp299 Gly variants were found when the age at onset was younger (p=0.018). A large number of concomitant diseases were observed. There was no difference in the prevalence of TLR4 variants nor ASCA or pANCA between the patients with or without concomitant diseases. Patients who progressed more often needed surgery as compared to patients who remained free of stenosing or fistulising disease (27/32 or 84% versus 3/35 or 8.6%, respectively, p<0.0001) and more often had concomitant immune-mediated diseases and a trend for more seroreactivity towards ASCA.
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PMID:Clustering of (auto)immune diseases with early-onset and complicated inflammatory bowel disease. 1867 Jul 86

Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn's disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD.
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PMID:Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease. 1872 68

The Toll-like receptor 4 is a key mediator of the innate immune response. Besides its main ligand, the Gram-negative bacterial lipopolysaccharides, other molecules such as heat-shock protein 60, oxidized low density lipoprotein and fibronectin can also bind to the receptor. Activation of the Toll-like receptor induces the production of proinflammatory cytokines. There is increasing evidence showing that the Toll-like receptor 4 plays a role not only in the immune reaction against infectious agents but also in chronic non-infectious inflammatory diseases, such as atherosclerosis, diabetes mellitus and inflammatory bowel disease. This review briefly summarizes recent knowledge on the Toll-like receptor 4, its common co-segregation polymorphisms and the impact of these polymorphisms on various human diseases.
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PMID:[Polymorphisms of the Toll-like receptor 4 gene and their potential role in infectious diseases and chronic inflammatory disorders]. 1880 65

During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.
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PMID:Hyaluronan receptors involved in cytokine induction in monocytes. 1885 67

Curcumin, an active ingredient of Curcumin longa mediates its anti-inflammatory effects through inhibition of NFkB. Several pathways including toll-like receptors (TLR) induce NFkB leading to inflammation. In this study, we investigated the effects of curcumin on the expression of TLR-4 and MyD88, the upstream signaling pathway in experimental colitis induced in the Sprague-Dawley male rats by intra-rectal administration of trinitrobenzenesulfonic acid (TNBS). The animals which received TNBS were divided into two groups: Group 1, received aqueous suspension of curcumin (100 mg/Kg body weight) 2 h prior to inducing colitis, and the treatment was repeated every day for 5 days, and Group 2 and non-colitis (Group 3) animals received phosphate buffered saline (PBS) in a similar fashion. Non-colitis animals (Group 4) received curcumin and served as controls. Animals were sacrificed on day 5 post-TNBS by cervical dislocation, colon was taken out, and cleaned with PBS. Levels of TLR-4, MyD88, and NFkB proteins were measured using ECL Western blot analysis, and TLR-4 mRNA by a competitive RT-PCR method. Colitis was confirmed histologically by measuring myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in the colonic tissues. TNBS-induced increase in the level of MPO activity and MDA concentrations was reversed by curcumin treatment, whereas the same dose of curcumin did not affect their levels in the non-colitis animals. Increases in the levels of TLR-4, MyD88, and NFkB proteins in inflamed tissue were also suppressed significantly by curcumin treatment. The level of TLR-4 mRNA remained unchanged in the colitis animals. These findings demonstrate that signaling pathway of curcumin-induced inhibition of inflammation involves TLR-4 and MyD88, and therefore may serve as an important therapeutic target in IBD.
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PMID:Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. 1900 62

Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (5HT), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1beta and Escherichia coli lipopolysaccharide (LPS) induced EC cell 5HT release through Toll-like/IL-1 (TIL) receptor activation, nuclear factor kappa B (NFkappaB) and mitogen-activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn's colitis (n = 6) mucosa. 5HT release was measured (ELISA), and NFkappaB and ERK phosphorylation quantitated (ELISA) in response to IL1beta and LPS. 5HT secretion was increased by both E. coli LPS (EC(50) = 5 ng mL(-1)) and IL1beta (EC(50) = 0.05 pmol L(-1)) >2-fold (P < 0.05) in Crohn's EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC(50) = 12 ng mL(-1)) and the IL1beta receptor antagonist (ILRA; IC(50) = 3.4 ng mL(-1)). IL1beta caused significant (P < 0.05) NFkappaB and MAPK phosphorylation (40-55%). The somatostatin analogue, lanreotide inhibited IL1beta-stimulated secretion in Crohn's (IC(50) = 0.61 nmol L(-1)) and normal EC cells (IC(50) = 1.8 nmol L(-1)). Interleukins (IL1beta) and bacterial products (E. coli LPS) stimulated 5HT secretion from Crohn's EC cells via TIL receptor activation (TLR4 and IL1beta). Immune-mediated alterations in EC cell secretion of 5HT may represent a component of the pathogenesis of abnormal bowel function in Crohn's disease. Inhibition of EC cell-mediated 5HT secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology.
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PMID:IL1beta- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn's disease. 1901 13


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