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)

In the current era, in inflammatory bowel disease step-up vs. top-down therapeutic approaches for the treatment of Crohn's disease (CD) are evaluated. As a consequence, we need to be able to differentiate between patients who will have more aggressive phenotypes to those with potentially more benign CD course. The former would require closer follow-up; however, more important might be the subgroup of patients to whom we want to offer biologic and immunomodulator therapy early on. This strategy is the only one supposed to prevent hospitalization and surgical intervention, specifically in patients with fistulae. Patients with expected fibrostenotic disease phenotype require early identification as well. The data regarding primary prevention of fibrostenosis are scarce; however, the association of biologic therapy with fewer surgeries might suggest that at least a subgroup of these patients would benefit from early, step-up therapeutic strategy. They might also benefit more from early immunomodulator therapy, as this was shown to have a secondary (though modest) preventive effect. The patients with fibrostenotic phenotype are also candidates for the most needed but still practically nonexistent anti-fibrotic therapies. In any case where patients are identified as having a higher chance to develop the more aggressive phenotypes, fibrostenotic and perforating, recommendation to avoid triggers/accelerators of disease progression (smoking, NSAIDS use) should be kept rigorously. Until recently, we based our attempts to predict disease phenotype mainly on clinical characteristics. As would be the case with many clinical features, some of them are not even predictors, but already manifestations of the condition we are trying to predict. Intervention at this stage might be too late for this patient. In addition to known demographic and clinical predictors reported, more recently sophisticated predictors shall be described. These predictors belong to three major groups: serologic markers, genetic markers, mucosal disease/healing. The major serologic markers used: anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (ANCA), outer membrane porin C (OmpC), CBir1-flagellin, antibodies against I2 protein and the anti-glycan antibodies: anti-laminaribioside carbohydrate (ALCA), anti-chitobioside carbohydrate (ACCA) and anti-mannobioside carbohydrate (AMCA) and their associations with penetrating and fibrostenotic disease shall be discussed. The associations of genetic polymorphisms such as CARD15 and TLR4 variants and more aggressive disease phenotype will be described as well. Finally, the data supporting the relationship between inflamed, in contrast to healed intestinal mucosa and more aggressive disease course will be illustrated. These predictors may be used in clinical practice and/or research in order to better stratify CD prognosis. Thus they may be significant in our therapeutic decisions. Models for using these predictors would be presented.
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PMID:Disease behavior in adult patients: are there predictors for stricture or fistula formation? 1978 42

The ocular surface epithelium serves a critical function as the defensive front line of the innate immune system. While the detection of microbes is arguably its most important task, an exaggerated host defense reaction to endogenous bacterial flora may initiate and perpetuate inflammatory mucosal responses. The ability of cells to recognize pathogen-associated molecular patterns (PAMPs) mainly depends on the expression of a family of Toll-like receptors (TLRs). A healthy ocular surface is not inflammatory, even though ocular surface epithelium is in constant contact with bacteria and bacterial products. In this study, we show that human ocular surface epithelial cells, both corneal and conjuctival epithelial cells, respond to viral double-stranded RNA mimic polyI:C to produce pro-inflammatory cytokines through TLR3, while they fail to respond functionally to lipopolysaccharide, a TLR4 ligand. Moreover, human ocular surface epithelium responds to flagellins from ocular pathogenic, but not ocular non-pathogenic bacteria, to produce pro-inflammatory cytokines through TLR5. Thus, ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation; immune-competent cells can recognize microbial components through TLRs and induce the inflammation. The unique innate immune response of the ocular surface epithelium may contribute to its coexistence with commensal bacteria. Inflammatory bowel disease is thought to result from an abnormal response to the gut microbiota. Thus, we also considered the possibility of an association between ocular surface inflammation and a disordered innate immune response. IkappaBzeta is important for TLR signaling, in mice, its knock-out produced severe, spontaneous ocular surface inflammation, the eventual loss of goblet cells, and spontaneous perioral inflammation, suggesting that dysfunction/abnormality of innate immunity can lead to ocular surface inflammation.
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PMID:Innate immunity of the ocular surface. 1982 29

Nearly 12% of children and 6% of adults in Canada have been diagnosed with asthma. Although in most patients symptoms are controlled by inhaled steroids, a subpopulation (approximately 10%) characterized by excessive airway neutrophilia, is refractory to treatment; these patients exhibit severe disease, and account for more than 50% of asthma health care costs. These numbers underscore the need to better understand the biology of severe asthma and identify pro-asthma mediators released by cells, such as neutrophils, that are unresponsive to common steroid therapy. This review focuses on a unique protein complex consisting of S100A8 and S100A9. These subunits belong to the large Ca2+-binding S100 protein family and are some of the most abundant proteins in neutrophils and macrophages. S100A8/A9 is a damage-associated molecular pattern (DAMP) protein complex released in abundance in rheumatoid arthritis, inflammatory bowel disease, and cancer, but there are no definitive studies on its role in inflammation and obstructive airways disease. Two receptors for S100A8/A9, the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), are expressed in lung. TLR4 is linked with innate immunity that programs local airway inflammation, and RAGE participates in mediating fibroproliferative remodeling in idiopathic pulmonary fibrosis. S100A8/A9 can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. We hypothesize that this capacity suggests S100A8/A9 could underpin chronic airway inflammation and airway remodeling in asthma by inducing effector responses of resident and infiltrating airway cells. This review highlights some key issues related to this hypothesis and provides a template for future research.
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PMID:S100A8/A9: a mediator of severe asthma pathogenesis and morbidity? 1989 58

There is growing evidence that aberrant innate immune responses towards the bacterial flora of the gut play a role in the pathogenesis of canine inflammatory bowel disease (IBD). Toll-like receptors (TLR) play an important role as primary sensors of invading pathogens and have gained significant attention in human IBD as differential expression and polymorphisms of certain TLR have been shown to occur in ulcerative colitis (UC) and Crohn's disease (CD). The aim of the current study was to evaluate the expression of two TLR important for recognition of commensals in the gut. TLR2 and TLR4 mRNA expression in duodenal biopsies from dogs with IBD was measured and correlated with clinical and histological disease severity. Endoscopic duodenal biopsies from 20 clinical cases and 7 healthy control dogs were used to extract mRNA. TLR2 and TLR4 mRNA expression was assessed using quantitative real-time PCR. TLR2 mRNA expression was significantly increased in the IBD dogs compared to controls, whereas TLR4 mRNA expression was similar in IBD and control cases. In addition, TLR2 mRNA expression was mildly correlated with clinical severity of disease, however, there was no correlation between TLR2 expression and histological severity of disease.
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PMID:Expression of Toll-like receptor 2 in duodenal biopsies from dogs with inflammatory bowel disease is associated with severity of disease. 2003 78

Mannose-binding lectin (MBL) is a major, soluble, pattern-recognition molecule and an important component of the innate host defense. The role of MBL in inflammatory bowel diseases (IBDs) is controversial. We determined the prevalence of MBL deficiency in a Hungarian IBD patients' cohort, and whether it is associated with the antimicrobial antibody formation or particular clinical manifestations. Nine hundred ninety IBD patients and 225 healthy subjects were investigated. Sera were assayed for MBL and a panel of antimicrobial antibodies (anti-OMP, anti-Saccharomyces cerevisiae antibodies, and antiglycans) by ELISA. TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism. Median MBL level was not significantly different between IBDs (Crohn's disease [CD]: 929; ulcerative colitis [UC]: 810 ng/ml) and the control group (1027 ng/ml), as well as the prevalence of absolute MBL deficiency (<100 ng/ml) (CD: 15.0%, UC: 18.4%, controls: 15.6%). The presence of a low MBL level (<500 ng/ml) was not associated with any of the examined serologic markers, or their combinations. In addition, there was no association with the clinical presentation, disease course, or response to treatment. TLR4 variant genotype was more common in CD patients without MBL deficiency (11% vs. 1.7%, OR: 7.29, 95% CI: 1.08-53.9, p = 0.02). We failed to confirm any association between MBL deficiency and serologic marker positivity. MBL deficiency was not predictive for clinical phenotype or disease activity in IBDs.
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PMID:Mannose-binding lectin level and deficiency is not associated with inflammatory bowel diseases, disease phenotype, serology profile, and NOD2/CARD15 genotype in a large Hungarian cohort. 2007 90

Pathogen recognition receptors (PRRs) function to maintain the balance between controlled responses to pathogens and uncontrolled innate immune activation leading to inflammation. In the context of commensal bacteria and the etiology of inflammatory bowel disease, although a role for the TLRs is known, there is a less defined function for C-type lectin receptors (CLRs). We demonstrate that mice deficient ((-/-)) in the CLR specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) (CD209b) have reduced susceptibility to experimental colitis, with a reduction in the disease severity, colon damage, and levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. To determine whether SIGN-R1(-/-) mice had a systemic defect in innate activation, we examined the responsiveness of macrophages from SIGN-R1(-/-) mice to TLR ligands. SIGN-R1(-/-) peritoneal macrophages, but not bone marrow-derived macrophages, have a specific defect in IL-1beta and IL-18 production, but not other cytokines, in response to the TLR4 ligand LPS. In vivo SIGN-R1(-/-) mice had significantly reduced susceptibility to LPS-induced shock. To address the synergistic relationship between SIGN-R1 and TLR4 in the context of experimental colitis, SIGN-R1/TLR4(-/-) mice were generated. SIGN-R1/TLR4(-/-) mice displayed reduced susceptibility to experimental colitis relative to severity of disease observed in wild-type or TLR4(-/-) mice. The in vivo use of a blocking mAb confirmed a functional role for SIGN-R1 in LPS-induced shock and experimental colitis. These data indicate a role for SIGN-R1 in the regulation of inflammation in a model of experimental colitis and illustrate that SIGN-R1 is a critical innate factor in response to LPS.
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PMID:C-type lectin SIGN-R1 has a role in experimental colitis and responsiveness to lipopolysaccharide. 2013 Feb 11

The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-alpha (TNF-alpha) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1beta (IL-1beta), TNF-alpha, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient.
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PMID:Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats. 2017 98

Many chronic inflammatory diseases are associated with increased risk of developing cancer. In the colon, strong support for a link between chronic inflammation and cancer extends, in part, from population-based studies of persons with inflammatory bowel disease (IBD). Patients with IBD are at increased risk of developing colorectal cancer (CRC). The general consensus is that IBD results from the combined effects of genetics and environment factors known to affect the immune system. Vitamin D, an important regulator of the immune system, has been linked to IBD. Despite the strong potential reported for 1,25-dihydroxyvitamin D (1,25-OH)2D), its effects on calcium metabolism limits its application. Recently, less active vitamin D metabolites, cholecalciferol and 25-hydroxyvitamin D (25(OH)D), have gained considerable attention as promising agents against IBD-related colon cancer. Yet, their anti-proliferative properties and mechanism of action remain to be better defined. We present several signaling pathways commonly regulated by vitamin D compounds and highlight their regulation on TLR4. The efficacy of 25(OH)D and 1alpha-hydroxyviatmin D5 are evaluated using the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced IBD-related colon carcinogenesis model. In summary, vitamin D supplementation may provide a cost-effective approach to reduce IBD related colon cancer.
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PMID:Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer. 2021 86

Myeloid differentiation (MD)-2 is linked to the cell surface as a Toll-like receptor (TLR) 4-bound protein though may also function as a soluble receptor to enable the lipopolysaccharide (LPS)-driven response. We recently demonstrated the importance of MD-2 either as a cell-associated or as a soluble receptor in the control of intestinal epithelial cell response toward LPS. High levels of circulating MD-2 were recently proposed as a risk factor for infectious/ inflammatory diseases as septic shock. We hypothesized that MD-2 might be present in sera from patients with inflammatory bowel disease and have pathogenic consequences. We analysed MD-2 activity in sera from patients with inflammatory bowel disease or from healthy subjects. We measured MD-2 activity as the capacity to mediate LPS-driven stimulation of intestinal epithelial cells (HT29). We found that sera from patients with inflammatory bowel disease, particularly Crohn's disease, endowed HT29 cells with a markedly higher LPS-dependent stimulating capacity as compared to sera from healthy subjects. The effect of sera was specific for LPS activation and was reduced in the presence of anti-MD-2, and anti-TLR4 antibodies. We conclude that sera from patients with inflammatory bowel disease might contain increased MD-2. This might result in higher local availability of the protein leading to a loss of tolerance toward gut microbiota.
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PMID:Sera from patients with Crohn's disease break bacterial lipopolysaccharide tolerance of human intestinal epithelial cells via MD-2 activity. 2084 44

There has been growing interest in the role of host genetic factors in humans and susceptibility to infectious and inflammatory diseases. Genetic variation in Toll-like receptors (TLRs), key innate immune receptors or their signalling molecules, have been described. Variation in certain TLRs has been linked to disease susceptibility. This genetic variation can result in an altered immune response to pathogenic challenge as well as exorbitant immune activation and inflammation, and thus may influence the pathogenesis or outcome of disease. Examples include variants of TLR4 in sepsis, malaria, inflammatory bowel disease and atherosclerosis; variants in TLR2 in tuberculosis and asthma; a variant in Mal (a key signal for TLR2 and TLR4) in malaria, tuberculosis and systemic lupus erythematosus; and variants in the kinase IRAK4 in pyogenic infections. These associations provide us with a validation for the role of TLRs in human disease, and also suggest possible strategies to limit or boost TLR function in the effort to develop new therapies.
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PMID:Genetic variation in Toll-like receptor signalling and the risk of inflammatory and immune diseases. 2037 92


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