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)

Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders.
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PMID:Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. 1108 26

Humans are constantly exposed to a wide variety of microorganisms that can cause infection. In self-defense, the human host has evolved complex protective mechanisms, and Toll-like receptors (TLRs) have emerged as a central point in defense. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host, eg, lipopolysaccharides (LPS) or double-stranded RNA (dsRNA). Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens may predispose the host to recurrent infections. The relative rarity of these syndromes of defective innate immunity, however, speaks to the redundancy in sensing of pathogens by the innate immune system. More common, polymorphisms in TLR4 are associated with increased predisposition to severe and recurrent infections but protection against atherosclerotic disease due to diminished inflammation. Toll-like receptor signaling may also contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response such as in sepsis or inflammatory bowel disease (IBD). The focus of this article is to describe the role of TLRs in the innate immune response in health and disease.
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PMID:Innate immunity and toll-like receptors: clinical implications of basic science research. 1506 87

Genes encoding for receptors of the innate immune system are potential candidates for susceptibility to inflammatory bowel disease, e.g., mutations in the cytosolic receptor NOD2/CARD15 were associated with Crohn's disease. Herein, two mutations of the Toll-like receptor (TLR)-4 gene (Asp299Gly and Thr399Ile) resulting in impaired lipopolysaccharide signaling, the -159C/T promotor polymorphism of the CD14 gene, polymorphisms of the lipopolysaccharide binding protein gene and the bactericidal permeability increasing protein gene were evaluated in 102 patients with Crohn's disease, 98 patients with ulcerative colitis and 145 healthy controls. The allele and carrier frequencies for the Thr399Ile mutation in TLR4 gene were significantly increased in ulcerative colitis when compared to the controls (P = 0.014 and P = 0.018, respectively). None of the other five polymorphisms was associated with inflammatory bowel disease. In conclusion, a novel association between a functional polymorphism in TLR4 and ulcerative colitis is reported. This observation underscores the importance of impaired innate immunity in inflammatory bowel disease.
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PMID:Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. 1520 85

Research efforts in the inflammatory bowel diseases have been uniquely successful in identifying genetic linkage regions likely containing susceptibility genes for Crohn's disease and ulcerative colitis. In two of these regions, definitive gene associations have been established, namely for the NOD2/CARD15 gene on chromosome 16 (IBD1) and the OCTN1/SLC22A4-OCT/SLC22A5 genes on chromosome 5q (IBD5), both conferring increased risk for developing Crohn's disease. Recently, significant gene associations have been reported for additional genes, including DLG5, MDR1, and TLR4 as well. The NOD2/CARD15 gene mutations are associated with ileal disease location and a modestly earlier age of onset compared with NOD2/CARD15 wild-type Crohn's disease patients. Future progress in the genetics of inflammatory bowel disease will likely involve systematic phenotyping, including the incorporation of clinical subtypes and novel biomarkers. The ultimate goal of genetic research in inflammatory bowel disease is to identify the earliest biologic pathways that are altered, resulting in disease pathogenesis. Identification of these key pathways will potentially highlight novel therapeutic targets.
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PMID:Advances in the genetics of inflammatory bowel disease. 1552 76

Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4-/- and MyD88-/- mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4-/- mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4-/- mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88-/- mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4-/- and MyD88-/- mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4-/- and MyD88-/- mice. The similarity in crypt epithelial damage between TLR4-/- or MyD88-/- and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.
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PMID:Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. 1582 31

Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.
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PMID:A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. 1587 43

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.
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PMID:Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. 1601 May 82

Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFbeta production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFbeta, but not TNF-alpha or IL-12. The TGFbeta derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFbeta secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFbeta through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.
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PMID:Heligmosomoides polygyrus induces TLR4 on murine mucosal T cells that produce TGFbeta after lipopolysaccharide stimulation. 1639 54

Intestinal epithelial cells (IEC) are constantly exposed to both high concentrations of the bacterial ligand LPS and the serine protease trypsin. MD-2, which contains multiple trypsin cleavage sites, is an essential accessory glycoprotein required for LPS recognition and signaling through TLR4. The aim of this study was to characterize the expression and subcellular distribution of intestinal epithelial MD-2 and to delineate potential functional interactions with trypsin and then alteration in inflammatory bowel disease (IBD). Although MD-2 protein expression was minimal in primary IEC of normal colonic or ileal mucosa, expression was significantly increased in IEC from patients with active IBD colitis, but not in ileal areas from patients with severe Crohn's disease. Endogenous MD-2 was predominantly retained in the calnexin-calreticulin cycle of the endoplasmic reticulum; only a small fraction was exported to the Golgi. MD-2 expression correlated inversely with trypsin activity. Biochemical evidence and in vitro experiments demonstrated that trypsin exposure resulted in extensive proteolysis of endogenous and soluble MD-2 protein, but not of TLR4 in IEC, and was associated with desensitization of IEC to LPS. In conclusion, the present study suggests that endoplasmic reticulum-associated MD-2 expression in IBD may be altered by ileal protease in inflammation, leading to impaired LPS recognition and hyporesponsiveness through MD-2 proteolysis in IEC, thus implying a physiologic mechanism that helps maintain LPS tolerance in the intestine.
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PMID:Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. 1654 63

Induction of inflammatory bowel (IBD)-like disease in mice by a targeted mutation in the Il10 gene (Il10(-/-)) is inbred strain dependent. C3H/HeJBir (C3) mice are colitis susceptible, whereas C57BL/6J (B6) mice are resistant. Genetic dissection of this susceptibility revealed 10 colitogenic quantitative trait loci (QTL). The aim of this study was to identify valuable candidate genes by a combination of QTL mapping and microarray analyses. Sixteen genes were differentially expressed between B6- and C3-Il10(-/-) mice and were located within the QTL intervals. Three major candidate genes (Cd14, Gbp1, Pla2g2a) showed prominent expression differences between B6- and C3-Il10(-/-) as well as between B6 and C3 wild-type mice, which was confirmed by semiquantitative or real-time RT-PCR. Because strain differences are known for Gbp1 and Pla2g2a, further analyses focused on Cd14. Western blot analysis revealed strain differences also on the protein level. Cd14 expression in animals with defective and intact Toll-like receptor (TLR)4 signaling (C3, C3H/HeN, B6, B6-Tlr4(tm1Aki)) make the TLR4 defect of C3 mice unlikely to be the reason for higher Cd14 expression. Less Cd14 expression in germ-free mice indicates a contribution of the microflora on Cd14 expression. Stimulation of naive peritoneal macrophages with bacterial antigens showed lower CD14 surface expression in B6 than in C3 mice. In conclusion, the large number of candidate genes was reduced to three major candidates that play an important role in inflammatory processes and immune response. Strain differences for them are already known or are shown in this study.
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PMID:Cd14, Gbp1, and Pla2g2a: three major candidate genes for experimental IBD identified by combining QTL and microarray analyses. 1670 22


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