Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Japan, nutritional therapy as both a primary and as a secondary treatment is widely used for Crohn's disease (CD). The rationale for its use is based on a variety of reasons. The first is its ability to induce remission and to ameliorate the activity of intestinal lesions in the short term by enteral (EN) or by parenteral nutritional therapy in which overexpressions of chemokine receptors in an active stage are decreased significantly in the remission stage. Second is its ability to maintain remission over the long term through home-based enteral nutrition in which tube feeding during the nighttime is encouraged. Third is its ability to reduce the steroid dosage over the period of a long-term treatment course. However, several disadvantages of this therapy such as unpalatability and sluggish effect have been pointed out. Several studies have attempted to resolve this issue and determine the best components of EN, especially in fat composition. Some data have been suggestive of too much long-chained fatty acid having a hazardous effect on EN's clinical efficacy because it works as a precursor of inflammatory prostaglandins. Our recent data show that medium-chained triglyceride did not have such a hazardous effect on clinical efficacy. Several studies suggested that the patient factors that were resistant to inducing remission in the short term were a long period of suffering CD, a high activity (on Crohn's Disease Activity Index, CDAI), hemorrhagic colitis, and colitis with marked cobblestoning. Japanese guidelines for the treatment of CD recommended nutritional therapy as a first-line therapy and as a maintenance therapy after inducing remission. This treatment policy has led to Japanese CD patients having lower mortality rates than that of patients who do not receive EN. If this therapy could be combined with other drug therapies, including strong immunosuppressants, treatment strategies would be improved over those we have at present.
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PMID:Nutritional therapy for Crohn's disease in Japan. 1590 60

The innate immune system plays a crucial role in maintaining the integrity of the intestine and protecting the host against a vast number of potential microbial pathogens from resident and transient gut microflora. Mucosal epithelial cells and Paneth cells produce a variety of antimicrobial peptides (defensins, cathelicidins, crytdinrelated sequence peptides, bactericidal/permeabilityincreasing protein, chemokine CCL20) and bacteriolytic enzymes (lysozyme, group IIA phospholipase A2) that protect mucosal surfaces and crypts containing intestinal stem cells against invading microbes. Many of the intestinal antimicrobial molecules have additional roles of attracting leukocytes, alarming the adaptive immune system or neutralizing proinflammatory bacterial molecules. Dysfunction of components of the innate immune system has recently been implicated in chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, illustrating the pivotal role of innate immunity in maintaining the delicate balance between immune tolerance and immune response in the gut.
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PMID:Innate defenses of the intestinal epithelial barrier. 1597 Nov 5

Chemokines are important mediators involved in the recruitment of leucocytes to lymphoid tissues and to sites of inflammation. To identify suitable monoclonal antibodies for immunohistochemistry, we tested a panel of new reagents provided by the cytokine/chemokine receptor section of the 8th HLDA workshop on cryostat sections of normal human gut, tonsil, and liver. In addition, inflamed intestinal tissues from individuals with Crohn's disease and ulcerative colitis were analysed. Our results reveal an upregulated expression of chemokine receptors like CCR6, CCR7, CCR9, CXCR1, and CXCR3 in inflamed gut. Enhanced expression of such molecules likely contributes to the maintenance of inflammation in chronic inflammatory bowel disease.
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PMID:Expression of chemokine receptors in normal and inflamed human intestine, tonsil, and liver--an immunohistochemical analysis with new monoclonal antibodies from the 8th international workshop and conference on human leucocyte differentiation antigens. 1618 74

The association of NOD2/CARD15 gene mutations with Crohn's disease (CD) has also provided proof of principle that anatomic location (ileal disease) and stricturing behavior is associated with specific genetic variants. However, the majority of CD patients of Caucasian descent, and essentially all minority CD patients do not possess NOD2/CARD15 mutations. Although these early lessons from NOD2/CARD15 genotype/phenotype correlations are encouraging, much more needs to be done to adequately understand the CD spectrum of subgroups. The study by Brand et al. demonstrates that a chemokine receptor polymorphism (CX3CR1 T280) can also influence disease location and behavior, suggesting yet another genetic variant that can help to subgroup CD patients. Findings similar to the study by Brand and colleagues in this issue of American Journal of Gastroenterology suggest that panels of susceptibility alleles and polymorphisms will ultimately allow an early genetic determination that will correspond with unique clinical patterns of CD: increased expression of the chemokine fractalkine in Crohn's disease and association of the factalkine receptor T280M polymorphism with a fibrostenosing disease phenotype.
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PMID:Molecular stratification of Crohn's disease by chemokine receptors: fractalkine receptor polymorphisms define a fibrostenosing ileal subgroup. 1640 41

The exact pathological background of inflammatory bowel disease has not been clarified yet. Many aspects of genetical and environmental factors, as well as certain alterations of the functions of epithelial cells and immunoregulation which may attenuate chronic inflammation in the gastrointestinal tract are known. These three components have many connecting points. Among the inflammatory bowel disease genes we know only the function of the NOD2/CARD gene, and we have some idea about the OCTN and DRG genes. The function of the intestinal epithelial cells is changed in inflammatory bowel disease. The latter two genes may have a role in the increased permeability, so as the tumor necrosis factor alpha, interferon gamma may play affect it. The interleukin-10 helps the mucosal integrity. The interleukin-6 production is elevated in these diseases, and the interleukin-8 level can be elevated in case of mutation of toll like receptor 5. The tumor necrosis factor alpha, interferon gamma and lymphotoxin-3-alpha increased the chemokine secretion and adhesion molecule expression also. The amount of certain cytokines are changed in inflammatory bowel disease. There were no association between the incidence and phenotype of Crohn's disease and cytokine gene polymorphisms, except the interleukin 6 gene. It seems that these alterations are secondary, and don't play a major role in the pathogenesis of inflammatory bowel disease.
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PMID:[Molecular biology background of inflammatory bowel disease]. 1697 77

Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's disease in animals and has been hypothesized to be associated with Crohn's disease in humans. Recently, M. avium subsp. paratuberculosis isolates recovered from Crohn's disease patients were shown to have limited diversity, implying the existence of human disease-associated genotypes and strain sharing with animals (A. H. Ghadiali et al., J. Clin. Microbiol. 42:5345-5348, 2004). To explore whether these genotypic differences or similarities among human and animal isolates translated to functionally significant attributes such as variance in host preference and/or difference in magnitude of infections, we performed a global scale analysis of M. avium subsp. paratuberculosis isolates that were representative of different genotypes and host species using DNA microarrays. Genome-wide characterization of the transcriptional changes was carried out using a human monocytic cell line (THP-1 cells) in response to different genotypes of M. avium subsp. paratuberculosis isolates recovered from various hosts. We identified several differentially expressed genes during early intracellular infection, including those involved in common canonical pathways such as NF-kappaB, interleukin-6 (IL-6), mitogen-activated protein kinase/extracellular signal-regulated kinase, and Jun N-terminal protein kinase signaling, as well as genes involved in T helper type 1 (Th1) responses (such as CCL5 ligand) and those that encode several proinflammatory cytokines and chemokine receptors. The cattle and human isolates of M. avium subsp. paratuberculosis, regardless of their short sequence repeat (SSR) genotype, induced similar global gene expression patterns in THP-1 cells. They differentially regulated genes necessary for cell survival without causing major alterations in proinflammatory genes. In contrast, the sheep isolates representing diverse SSR genotypes closely resembled the global gene expression pattern of an M. avium subsp. avium isolate, and they significantly up-regulated proinflammatory genes related to IL-6, T-cell receptor, B-cell receptor, and death receptor signaling within THP-1 cells. Additionally, we demonstrated consistency among infecting genotypes of M. avium subsp. paratuberculosis isolated from diverse hosts [cattle (n=2), human (n=3), sheep (n=2), and bison (n=1)] in quantitative reverse transcription-PCR analysis of seven differentially expressed genes. While the levels of expression induced by the bison isolate were different compared with cattle or human isolates, they followed the common anti-inflammatory, antiapoptotic trend. Our data suggest that the macrophage responses to M. avium subsp. paratuberculosis isolates from cattle and human sources, regardless of genotype, follow a common theme of anti-inflammatory responses, an attribute likely associated with successful infection and persistence. However, these expression patterns differ significantly from those in THP-1 cells infected with sheep isolates of M. avium subsp. paratuberculosis or the M. avium subsp. avium isolate. These data provide a transcriptional basis for a variety of pathophysiological changes observed during early stages of infection by different strains of M. avium subsp. paratuberculosis, a first step in understanding trait-allele association in this economically important disease.
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PMID:Comparative transcriptional analysis of human macrophages exposed to animal and human isolates of Mycobacterium avium subspecies paratuberculosis with diverse genotypes. 1705 86

We have applied an efficient solid-phase protein refolding method to the milligram scale production of natively folded recombinant chemokine proteins. Chemokines are intensely studied proteins because of their roles in immune system regulation, response to inflammation, fetal development, and numerous disease states including, but not limited to, HIV-1/AIDS, cancer metastasis, Crohn's disease, asthma and arthritis. Many investigators use recombinant chemokines for research purposes, however these proteins partition almost exclusively to the inclusion body fraction when produced in Escherichia coli. A major hurdle is to correctly refold the chemokine and oxidize the two highly conserved disulfide bonds found in nearly all chemokines. Conventional methods for oxidation and refolding by dialysis or extreme dilution are effective but slow and yield large volumes of dilute chemokine. Here we use an on-column approach for rapid refolding and oxidation of four chemokines, CXCL12/SDF-1alpha (stromal cell-derived factor-1alpha), CCL5/RANTES, XCL1/lymphotactin, and CX3CL1/fractalkine. NMR spectra of SDF-1alpha, RANTES, lymphotactin, and fractalkine indicate these chemokines adopt native structures. On-column refolded SDF-1alpha is fully active in an intracellular calcium flux assay. Our success with multiple SDF-1alpha mutants and members of all four chemokine subfamilies suggests that on-column refolding is a robust method for preparative-scale production of recombinant chemokine proteins.
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PMID:On-column refolding of recombinant chemokines for NMR studies and biological assays. 1707 Nov 4

A characteristic feature of human inflammatory bowel disease, particularly Crohn's disease, is the presence of activated CD4(+) T cells. Recently, we have shown that colonic epithelial cell production of macrophage inflammatory protein (MIP)-3alpha, a CD4 T cell-directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3alpha production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3alpha production is increased during murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and to examine the effect of anti-MIP-3alpha neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3alpha protein levels in Balb/c mice. Consistent with this, a marked increase in the number of CCR6-bearing lamina propria CD4(+) and CD8(+) T cells was also observed in TNBS-treated animals. Treatment of mice with an anti-MIP-3alpha neutralizing monoclonal antibody significantly reduced TNBS-mediated increases in colonic weight-to-length ratio, mucosal ulceration, histological damage, and myeloperoxidase activity. TNBS-mediated increases in the number of CCR6-bearing lamina propria T cells were also substantially reduced by anti-MIP-3alpha neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3alpha bioactivity can significantly reduce TNBS-mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.
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PMID:MIP-3alpha neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice. 1727 17

CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn's disease (CD) and an increased frequency of CCR9(+) T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9(+) T cells in mucosal lymphoid tissues in CD. We show that CCR9(+) T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9(+) T cells isolated from CD SB lamina propria produced more IFN-gamma and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-gamma, but not IL-17, by CD lamina propria CCR9(+) T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVbeta analysis of CCR9(+) T cells revealed a diverse TCRVbeta repertoire among MLN CCR9(+) T cells in patients with SB CD. Our data indicate that CCR9(+) T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.
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PMID:Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease. 1731 80

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides belonging to the VIP/secretin/glucagon family of peptides. VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and exert a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4(+) T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are perfectly known. Therefore, VIP/PACAP and analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson's disease, Crohn disease, or autoimmune diabetes. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system; and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as an exciting new candidate for therapeutic intervention and drug development.
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PMID:Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. 1743 Jan 75


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