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

It is becoming increasingly apparent that the chronic gut inflammation observed in the idiopathic inflammatory bowel diseases (e.g. ulcerative colitis, Crohn's disease) is associated with enhanced production of leukocyte-derived oxidants. Oxidants such as hydrogen peroxide are known to activate certain transcription factors such as nuclear transcription factor kappa beta. Nuclear transcription factor kB (NF-kappa B) is a ubiquitous transcription factor and pleiotropic regulator of numerous genes involved in the immune and inflammatory responses. This transcription factor is activated via the selective phosphorylation, ubiquination and degradation of its inhibitor protein I-kB thereby allowing translocation of NF-kappa B into the nucleus where it upregulates the transcription of a variety of adhesion molecules (e.g. ICAM-1, VCAM-1), cytokines (TNF, IL-1, IL-6) and enzymes (iNOS). The proteolytic degradation of the post-translationally modified I-kappa B is known to be mediated by the 26S proteasome complex. Based upon work from our laboratory, we propose that inhibition of NF-kappa B activation produces significant anti inflammatory activity which may be mediated by the inhibition of transcription of certain pro-inflammatory mediators and adhesion molecules.
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PMID:Oxidant-regulation of gene expression in the chronically inflamed intestine. 909 77

It is postulated that an enhanced production of nitric oxide by inflamed intestine plays a role in the pathophysiology of active inflammatory bowel disease. In this study, systemic NOx concentrations and colonic nitric oxide synthase activity were determined in patients with ulcerative colitis or Crohn's disease. The relationship between these two parameters and disease activity, as well as differences in nitric oxide synthase activity between ulcerative colitis and Crohn's disease, were areas of specific focus. Patients with active ulcerative colitis and Crohn's disease had significantly elevated plasma NOx concentrations; a positive correlation was found between NOx values and inducible nitric oxide synthase activities in the active mucosa of these patients. In active ulcerative colitis, levels of inducible nitric oxide synthase were significantly elevated in both normal and inflamed mucosa, although inducible nitric oxide synthase activity was higher in the latter. These colonic inducible nitric oxide synthase activities correlated well with the results of endoscopic and histologic grading of inflammation. There was no increase in constitutive nitric oxide synthase activity in patients with active ulcerative colitis. However, constitutive nitric oxide synthase activity was significantly increased in the inflamed mucosa in patients with Crohn's disease. In Crohn's disease, elevated inducible nitric oxide synthase activity was found in both normal and inflamed mucosa, with no significant difference between the tissues. Such differences in nitric oxide production in the colonic mucosa possibly reflect the significant differences in the pathophysiology and characteristic clinical features between ulcerative colitis and Crohn's disease.
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PMID:Increased nitric oxide production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn's disease. 914 61

The plasma protein alpha 2-macroglobulin (alpha 2M) has been reported to bind the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta), which play a central role in the pathogenesis of chronic inflammatory disorders, including Crohn's disease and rheumatoid arthritis. In this study, we chemically modified alpha 2M to stabilize a conformation of the protein (termed MAC, Macroglobulin Activated for Cytokine binding) with greatly increased TNF-alpha- and IL-1 beta-binding activity. The equilibrium dissociation constant (KD) for the binding of TNF-alpha to MAC was 80 +/- 20 nM, reflecting a 100-fold increase in affinity compared with native alpha 2M. To test the ability of MAC to neutralize proinflammatory cytokines in vivo, we treated mice with lipopolysaccharide (LPS) by intravenous injection. When MAC (2.5 mg) was administered by intraperitoneal injection 1 hour before the LPS, 12 of 12 mice survived and were without signs of toxicity at 5 days. None of the mice survived in the untreated control group (0/26) or in the group treated with 2.5 mg of unmodified alpha 2M (0/4). MAC also prevented the large increase in expression of inducible nitric oxide synthase in the liver, kidneys, and heart of LPS-treated mice. A novel property of MAC, compared with previously studied anticytokine agents, was its ability to reverse LPS toxicity in 12 of 24 mice when administered after the plasma level of TNF-alpha was elevated. These studies demonstrate that a naturally occurring protein, alpha 2M, can be modified so that it acquires the properties of clinically active monoclonal antibodies. Thus, MAC may have therapeutic potential in the control of chronic inflammatory disorders.
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PMID:A modified human alpha 2-macroglobulin derivative that binds tumor necrosis factor-alpha and interleukin-1 beta with high affinity in vitro and reverses lipopolysaccharide toxicity in vivo in mice. 971 81

Immunohistochemistry has been critical in determining the tissue localization of inducible nitric oxide synthase (iNOS). However, this technique suffers from nonspecific staining which may lead to false-positive results and the failure of antisera to recognize iNOS from different species. We developed a technique to determine the localization of iNOS mRNA, as opposed to protein, in tissue sections using an in situ RT-PCR (IS RT-PCR) technique. Sections of inflamed gastrointestinal mucosa were used because they were known to be positive for iNOS. The IS RT-PCR technique localized iNOS mRNA to the same sites as immunoreactive iNOS in human gastritis associated with Helicobacter pylori infection, Crohn's disease, and experimental inflammatory bowel disease induced by the hapten TNBS, in rat colon and in guinea pig ileum. The detection of mRNA had an excellent signal-to-noise ratio. Preservation of tissue morphology was poorer than that with immunohistochemistry due the cycles of heating required in the PCR process. This method could be very useful in detecting iNOS gene expression in situations of excessive nonspecific staining with immunohistochemistry or of failure of antibodies to react because of species differences. This technique is also readily applicable to detect RNA and DNA markers of other disease processes.
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PMID:Localization of inducible nitric oxide synthase mRNA in inflamed gastrointestinal mucosa by in situ reverse transcriptase-polymerase chain reaction. 973 36

Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn's disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO, and toxic megacolon, a complication of chronic colitis characterized by acute colonic dilatation, is associated with an enhanced intestinal synthesis of NO. The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis. The possible therapeutic role of selective iNOS inhibitors is still under investigation.
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PMID:Nitric oxide and inflammatory bowel diseases. 982 33

The aetiology of the chronic inflammatory bowel diseases-ulcerative colitis and Crohn's disease-as well as 'microscopic colitis'-both collagenous (COC) and lymphocytic colitis (LC)-remains unknown. Autoimmune mechanisms, cytokine polymorphism, commensal bacteria, infectious agents and vascular impairment have all been proposed as playing important roles in the pathogenesis of this spectrum of diseases. A variety of proinflammatory mediators, including tumour necrosis factor alpha, interleukin-1beta, interferon gamma, leukotriene B4 and platelet activating factor, promote the adherence of phagocytes to the venular endothelium and extravasation of these cells into the colonic mucosa. In addition to large amounts of nitric oxide (NO), injurious peroxynitrite may be formed in the epithelium by the inducible nitric oxide synthase (iNOS), which is considered to elicit cytotoxicity by the generation of superoxide with reduced L-arginine availability. In active ulcerative colitis, and to a lesser extent in Crohn's disease, a greatly increased production of NO has been demonstrated by indirect and direct measurements. Surprisingly, even higher rates of production have been observed in COC-a condition which is never associated with injurious inflammation. The latter observation favours the notion that NO promotes mucosal integrity. Further evidence for a protective role of NO in chronic inflammatory bowel disorders is provided by the observation of increased susceptibility to the induction of experi mental colitis in 'knock-out' mice deficient in iNOS. Selective inhibitors of iNOS activity, as well as topical L-arginine, may therefore prove beneficial in inflammatory bowel disease by reducing the production of superoxide by iNOS, while only the former option may be expected to reduce diarrhoea in chronic inflammatory bowel disorders. Clearly, further experimental work needs to be done before testing topical L-arginine in human inflammatory bowel disease.
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PMID:Review article: the potential role of nitric oxide in chronic inflammatory bowel disorders. 1010 42

Nitric oxide (NO) and reactive oxygen species (ROS) are important mediators in the pathogenesis of inflammatory bowel disease (IBD). NO in IBD can be either harmful or protective. NO can react with superoxide anions (O2.-), yielding the toxic oxidizing agent peroxynitrite (ONOO-). Peroxynitrite induces nitration of tyrosine residues (nitrotyrosine), leading to changes of protein structure and function. The aim of this study was to identify the cellular source of inducible nitric oxide synthase (iNOS) and to localize superoxide anion-producing cells in mucosal biopsies from patients with active IBD. Additional studies were performed to look at nitrotyrosine formation as a measure of peroxynitrite-mediated tissue damage. For this, antibodies against iNOS, endothelial NOS (eNOS), and nitrotyrosine were used. ROS-producing cells were detected cytochemically. Inflamed mucosa of patients with active IBD showed intense iNOS staining in the epithelial cells. iNOS could not be detected in non-inflamed mucosa of IBD patients and control subjects. eNOS was present in blood vessels, without any difference in the staining intensity between IBD patients and control subjects. ROS-producing cells were increased in the lamina propria of IBD patients; a fraction of these cells were CD15-positive. Nitrotyrosine formation was found on ROS-positive cells. These results show that iNOS is induced in epithelial cells from patients with active ulcerative colitis or Crohn's disease. Nitration of proteins was detected only on the ROS-producing cells at some distance from the iNOS-producing epithelial cells. These findings indicate that tissue damage during active inflammation in IBD patients is probably more related to ROS-producing cells than to NO. One may speculate that NO has a protective role when during active inflammation other mucosal defence systems are impaired.
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PMID:Expression of nitric oxide synthases and formation of nitrotyrosine and reactive oxygen species in inflammatory bowel disease. 1020 92

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-kappaB). The block to NF-kappaB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-kappaB, IkappaB-alpha and IkappaB-beta. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFN gamma induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN gamma production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF alpha, IFN gamma and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4+ Th1 cells in conjunction with activated macrophages.
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PMID:Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. 1048 79

Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.
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PMID:Inhibition of poly(ADP-ribose) polymerase attenuates inflammation in a model of chronic colitis. 1096 Mar 65

Infection with Toxoplasma gondii is naturally acquired through the oral route by ingestion of undercooked or raw meat containing cysts of the parasite or through ingestion of contaminated water or food contaminated with cysts or oocysts. Following peroral infection with 100 cysts of the ME49 strain of T. gondii, C57BL/6 mice die within 13 days after infection, whereas BALB/c mice survive. At day 7 of infection, massive necrosis of the villi and mucosal cells in the ilea is observed in C57BL/6 but not BALB/c mice. CD4(+) T cells, interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase mediate the development of necrosis. These findings indicate a Th1-type immunopathology, with parasite replication appearing to be involved in the first 3 days of infection. Murine and human studies on the immunopathogenesis of inflammatory bowel disease (e.g., Crohn's disease) also indicate a Th1-type immunopathology. The shared and distinct features of oral infection of mice with T. gondii and murine models of inflammatory bowel disease are discussed herein.
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PMID:Oral infection of C57BL/6 mice with Toxoplasma gondii: a new model of inflammatory bowel disease? 1186 46


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