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)

Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamily. The binding of OM to its receptor initiates signal transduction through JAK-signal transducers and activators of transcription (STAT) pathways and activates transcription activators through mitogen-activated protein (MAP) kinases. Results of in vitro assays documented that OM modulates cytokine expression and alters the production of proteases that down-regulate inflammation. Administration of OM to lipopolysaccharide (LPS)-challenged mice lowered serum tumor necrosis factor-alpha (TNF-alpha) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in animal models of human disease, including inflammatory bowel disease, antibody-induced arthritis, and experimental autoimmune encephalomyelitis. Preclinical safety studies have been conducted in the mouse and monkey. Mice were administered OM (subcutaneously) at 72, 360, or 1,560 micrograms/kg/day in a 2-wk toxicity study. Decreased body weights occurred at 1,560 micrograms/kg. Drug-related changes at 360 and 1,560 micrograms/kg consisted of dermal irritation at the injection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study in monkeys, OM was administered at 1, 5, 15, 45, or 150 micrograms/kg/day. At all doses there was reversible, transient inappetence and dermal irritation at the injection site. Drug-related changes at 5, 15, 45, and 150 micrograms/kg consisted of reversible elevations in both serum amyloid A and IL-6, and reversible thymic lymphoid depletion. Transient increases in body temperature occurred at 15, 45, and 150 micrograms/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.
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PMID:Oncostatin M: development of a pleiotropic cytokine. 1020 78

Inflammatory cytokines of the tumor necrosis factor (TNF) family mediate a large variety of cellular and organismal inflammatory responses and are important to the pathogenesis of a number of important disease states including arthritis, septic shock, inflammatory bowel disease, and, possibly, type II diabetes. Many of the responses to these cytokines require de novo gene expression mediated by the activator protein-1 (AP-1) heterodimeric transcription factor. This review will discuss what is known of how cytokines of the TNF family, acting at the cell surface, recruit two mitogen-activated protein kinase (MAPK) subfamilies, the stress-activated protein kinases (SAPKs, also called JNKs) and the p38s, to transduce signals to AP-1.
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PMID:Activation of the AP-1 transcription factor by inflammatory cytokines of the TNF family. 1044 Feb 23

The specific role of the tumor necrosis factor (TNF)/TNF receptor (TNFR) system in disease pathogenesis still remains an unresolved puzzle. Recent studies in transgenic and knockout animals, where the pathogenic influence of genetically perturbed TNF expression has been evaluated, indicate that several pathways of TNF/TNFR action may contribute independently or in concert to initiate, promote or downregulate disease pathogenesis. Evidently, organ-specific inflammatory or autoimmune pathology may ensue due to sustained activation by TNF of innate immune cells and inflammatory responses, which may consequently lead to tissue damage and to organ-specific chronic pathology. However, more cryptic functions of this molecule may be considered to play a significant part in the development of TNF-mediated pathologies. Direct interference of TNF with the differentiation, proliferation or death of specific pathogenic cell targets may be an alternative mechanism for disease initiation or progression. In addition to these activities, there is now considerable evidence to suggest that TNF may also directly promote or downregulate the adaptive immune response. It is therefore evident that no general scenario may adequately describe the role of TNF in disease pathogenesis. In this article, we aim to place these diverse functions of TNF/TNFRs into context with the development of specific pathology in murine models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.
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PMID:On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. 1045 May 17

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

The etiology and pathogenesis of inflammatory bowel disease (IBD) remains an area under intense investigation. Cytokine secretion, which is important in the regulation of normal gastrointestinal immune responses, appears to be dysregulated in IBD. In Crohn's disease, there appears to be an excessive T(H)1 T-cell response to an antigenic stimulus, leading to increased levels of proinflammatory cytokines, such as interferon-gamma (IFN-gamma), interleukin (IL)-12, IL-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In ulcerative colitis, a T(H)2 T-cell response appears to be the pathological process responsible for the inflammatory disease. New and innovative therapeutic strategies targeting cytokines, such as TNF-alpha, are producing some promising results in animal and human studies. As more is learned about the complex cytokine interactions in IBD, more effective treatments will undoubtedly ensue.
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PMID:Cytokines and inflammatory bowel disease: a review. 1048 88

Recent studies support nuclear factor-kappaB (NF-kappaB) as a critical transcription factor in inflammatory bowel disease. We examined NF-kappaB and its inhibitors, IkappaB-alpha and IkappaB-beta, in the colitis of interleukin-2 deficient (IL-2-/-) mice at the ages of 5, 10, and 15 weeks and compared them with those of age-matched wild-type mice. Colon levels of nuclear NF-kappaB and mRNA for NF-kappaB responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were markedly increased in interleukin-2-/-mice. Colon interleukin-1beta protein levels were significantly elevated, consistent with increased interleukin-1beta mRNA, whereas tumor necrosis factor-alpha protein levels were either lower than those of the control group or did not differ. Protein levels of the immunomodulatory cytokine interleukin-10 were diminished. The NF-kappaB responsive IkappaB-alpha was also increased, mirroring NF-kappaB activation. In contrast, IkappaB-beta levels did not differ from those of wild-type mice in the 5- and 10-week groups and were only mildly increased in the 15-week group. Serum amyloid A, an acute phase protein that also is NF-kappaB-responsive, was dramatically elevated in the serum of interleukin-2-/- mice and correlated with the severity of the colitis. These data support a role for NF-kappaB in the pathogenesis of intestinal inflammation in interleukin-2-/- mice. The measurement of NF-kappaB in colon tissue samples may provide a sensitive means of assessing the state of activation of the mucosal immune response, and serum amyloid A appears to be a reliable biochemical marker of disease activity.
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PMID:Increased nuclear factor-kappaB activation in colitis of interleukin-2-deficient mice. 1052 Oct 84

The normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents. However, patients with inflammatory bowel disease experience enhanced intestinal permeability that correlates with the degree of injury. IL-10 gene-deficient mice were studied to determine whether increased intestinal permeability occurs as a primary defect before the onset of mucosal inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene-deficient mice show an increase in ileal and colonic permeability in the absence of any histological injury. This primary permeability defect is associated with increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha, and does not involve an increase in nitric oxide synthase activity. Colonic permeability remains elevated as inflammation progresses, while ileal permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under germ-free conditions have no inflammation, and demonstrate normal permeability and cytokine levels. This data suggests that the intestinal permeability defect in IL-10 gene-deficient mice occurs due to a dysregulated immune response to normal enteric microflora and, furthermore, this permeability defect exists prior to the development of mucosal inflammation.
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PMID:Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. 1057 19

Several studies have indicated the involvement of macrophages and dendritic cells in active inflammatory bowel disease (IBD). Manipulation of these cells is considered a very important therapeutic strategy for patients with IBD. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with poly(DL-lactic acid) microspheres containing dexamethasone (Dx). Colitis was induced in BALB/c mice by 5% dextran sodium sulfate. Dx microspheres (n = 10) and only Dx (n = 10) were orally administered to dextran sodium sulfate-treated mice. Thereafter, serum levels and tissue distributions of Dx were investigated. To estimate the efficacy of this drug delivery system, we measured the histological score, myeloperoxidase activity and nitric oxide production, and gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma in the colonic tissue. Serum Dx levels were not increased after oral administration of Dx microspheres. The tissue distribution of microspheres containing (125)I-labeled Dx in inflamed colon was significantly higher than in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of the group treated with Dx microspheres were significantly lower than of those treated with Dx alone. Gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma were down-regulated in mice treated with Dx microspheres. Microspheres containing glucocorticoids such as Dx, which target microfold cells and macrophages, can facilitate mucosal repair in experimental colitis and could be an ideal agent for treatment of human IBD.
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PMID:Development of an oral drug delivery system targeting immune-regulating cells in experimental inflammatory bowel disease: a new therapeutic strategy. 1060 27

The role of cell-mediated cytotoxicity in the pathogenesis of ulcerative colitis and Crohn's disease has been controversial since reports indicating either a decreased, or an increased, activity of cytotoxic T cells in active stages of inflammatory bowel disease exist. Some of these discrepancies may be attributed to the fact that so far mostly peripheral blood lymphocytes rather than intestinal T cells have been examined. To overcome some of these limitations we performed in situ hybridizations for the detection of perforin and granzyme A mRNA expressing cells, i.e. of cytotoxic cells activated in situ, in the affected intestinal mucosa. These studies revealed increased frequencies of activated, cytotoxic T cells in active stages of ulcerative colitis and Crohn's disease. Interestingly, activated perforin mRNA expressing T cells are present both in the CD4 and in the CD8 T cell subsets. In the latter T cell subset up to 60% of the mucosal T cells isolated from the affected sites express perforin mRNA at detectable levels. The elevated frequency of activated cytotoxic cells and their histological distribution also in close proximity to the epithelial cells may thus indicate an important role for cytotoxic cells in the pathogenesis of inflammatory bowel disease since activated cytotoxic T cells may further exacerbate the inflammatory process through the production of pro-inflammatory cytokines such as interferon-gamma or tumor necrosis factor-alpha, but also through the release of pro-inflammatory cytokines and chemokines upon lysis of epithelial cells and the increased influx of luminal antigens at the site of epithelial erosions.
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PMID:The role of activated cytotoxic T cells in inflammatory bowel disease. 1066 7

This article reviews important papers on inflammatory bowel disease published between May 1998 and June 1999. It does not review every aspect of treatment, but focuses on the effects of anti-tumor necrosis factor antibodies on the inflammatory lesions. The new information summarized includes: the role of bacteria and the modulating effects of probiotics; the frequency of appendiceal orifice inflammation in ulcerative colitis; progress in imaging based on endoscopic ultrasonography, magnetic resonance imaging, and leukocyte scintigraphy; frequency and treatment of massive hemorrhage, viral superinfection, and persistent perineal sinus; and the pathogenesis, detection, and treatment of dysplasia and cancer.
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PMID:Inflammatory bowel disease. 1069 41


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