Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mucosal immune system consists of a number of compartments that are populated with a different assortment of cells and serve different functions. The cytokines produced by the cells in each of these compartments are currently being defined. This is best understood in relation to B cells, whose proliferation and maturation is guided by a sequence of cytokines. PP are inductive sites that preferentially stimulate IgA production. At least in part, this preference seems to be due to the T cells located in PP, which have been shown to stimulate switching to IgA production by cognate interactions and production of TGF-beta. Postswitch B cells expressing surface IgA respond to IL-5, a cytokine produced by T cells in GALT. Terminal differentiation to IgA-producing plasma cells in the lamina propria may be driven by IL-6, which can be produced by a variety of cells in the lamina propria and by epithelial cells. T cells in the lamina propria have an assortment of surface markers consistent with both activation and memory and appear to produce a variety of cytokines in the local environment that presumably act in normal host defense. IEL consist mainly of CD8+ T cells. They have been shown to produce IFN-gamma and, very likely, other cytokines that presumably act in a paracrine fashion on local enterocytes. How these cells and cytokines are perturbed during intestinal inflammation is currently being defined. A certain assortment of cytokines are greatly increased in IBD. This assortment, including IL-1, IL-6, and IL-8, is elevated in a wide variety of chronic inflammatory states in other tissues as well. A critical requirement for cytokines to exert their effects is the expression of specific receptors on target cells. Virtually nothing is known about this aspect of mucosal immunity, but receptor expression on mucosal cells must be defined before we will be able to understand the complex interactions among lymphoid cells, the cytokines they produce, and the local stromal and epithelial cells.
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PMID:Cells and cytokines in mucosal immunity and inflammation. 151 47

A toddler with common variable hypoimmunoglobulinemia (CVH), inflammatory bowel disease, and recurrent Pneumocystis carinii pneumonia (PCP) on intravenous gammaglobulin (IVIG) replacement was evaluated for a combined cellular immunodeficiency. He had a normal number of circulating T-cells, natural killer (NK) cells, T-cell subset percentages, and his peripheral blood mononuclear (PBM)-derived B-cell number was low. PBM mitogen blastogenesis and mixed lymphocyte reaction (MLR) were normal. MLR activated T-cells expressed class I and II MHC antigens, interleukin 2 (IL-2), and B-cell growth factor (IL-5)-related receptors. The patient's T-cells induced control B-cell maturation with pokeweed mitogen (PWM-PC), and did not suppress PWM-PC production by allogeneic PBM. Bone marrow (BM) CD19+ B-cell number varied between 10 and 44% of all PBM, and the BM B-cell-enriched fraction failed to differentiate to PWM-PC with autologous or allogeneic T-cell help. The NK activity assayed using K562 target cells was deficient, 9.2 x 7.7% (6.9-9.2%) pt, control 35.9 x 35.8% (16.3-67.2% +/- 12.8). In the presence of interferon-alpha, 800 U/ml, the patient's NK activity increased to 17.2 x 14.9% (12.6-17.2%), control 35.9 x 51.0% (36.5-72.3% +/- 12.0). The patient's cell-mediated lympholysis of HLA nonidentical, allogeneic stimulators was normal. Maintaining trough serum IgG levels above 500 mg/dl was required to suppress recurrent PCP. This functional NK deficiency may be relevant to the development of recurrent PCP in IVIG-treated CVH patients.
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PMID:Common variable hypogammaglobulinemia, recurrent Pneumocystis carinii pneumonia on intravenous gamma-globulin therapy, and natural killer deficiency. 278 54

In this study, we investigate whether human inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is associated with altered lymphokine secretion profiles, as recently found in various animal models of chronic intestinal inflammation. In initial studies, we determined the proliferative responses of purified lamina propria (LP) CD4+ T cells from patients with IBD under defined conditions of T cell stimulation. We found that IBD LP CD4+ T cells in comparison with control LP CD4+ T cells have diminished TCR/CD3 pathway proliferative responses, whereas CD2/CD28 accessory pathway proliferative responses are relatively preserved. In further studies centering on lymphokine production, we showed that LP T cells from inflamed Crohn's disease mucosa manifest increased IFN-gamma secretion compared with control LP T cells, particularly when stimulated via the CD2/CD28 pathway. Subsequent ELISPOT analysis indicated that this was due to an increased number of IFN-gamma-secreting CD4+ T cells. In contrast, IL-4 and IL-5 production by Crohn's disease LP T cells was decreased compared with that of control LP T cells. Of interest, IL-2 production by Crohn's disease LP T cells was also reduced, as was IL-2 production by peripheral blood T cells. In parallel studies, LP T cells from inflamed ulcerative colitis mucosa stimulated via either the TCR/CD3/CD28 or CD2/CD28 produced increased amounts of IL-5, again when measured either as secreted IL-5 or by ELISPOT analysis. Such increased IL-5 production was not associated with increased IL-4 secretion and, in contrast to Crohn's disease, ulcerative colitis LP T cell production of IL-2 and IFN-gamma was normal. Taken together, these studies provide strong evidence that the immunopathologic process characteristic of the two major forms of IBD is associated with very different cytokine secretion patterns. These different patterns may determine the type of inflammatory process present.
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PMID:Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. 875 34

Because both asthma and inflammatory bowel disease are chronic relapsing inflammatory conditions, comparisons are inevitable. Both disorders reflect the convergence of environmental trigger factors in genetically predisposed individuals. The genetic preposition may be on a polygenic basis or on the basis of genetic heterogeneity. Environmental factors that may trigger the expression or relapse in asthma and inflammatory bowel disease include: cigarette smoking (in Crohn's but not in ulcerative colitis), the use of non-steroidal anti-inflammatory drugs in asthma and Crohn's disease), infection and possibly stress. TH lymphocytes are currently believed to be important in asthma and in Crohn's disease but not in ulcerative colitis. IgE-activated eosinophils and mast cells are central to the maintenance of asthma but do not play such a crucial role in inflammatory bowel disease. TH2 cytokines including IL-4 and IL-5 are believed to be important in the inflammatory response of asthma, and TH cytokines are believed to be in Crohn's disease but a TH1 or TH2 subclassification is not currently evident. The hallmark of asthma is increased reactivity of the airways, in terms of bronchoconstriction. Altered physiology also accompanies inflammatory bowel disease but hyperactivity is not an invariable feature. Finally, it is becoming increasingly evident that neural influences modulate inflammatory processes and this is likely to be relevant to both asthma and inflammatory bowel disease.
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PMID:Similarities and dissimilarities between asthma and inflammatory bowel diseases. 889 98

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.
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PMID:Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. 889 6

Mice with targeted deletion of the G protein G(alpha)i2 develop an inflammatory bowel disease closely resembling ulcerative colitis. To better define disease pathogenesis, the mucosal immune system in G(alpha)i2-deficient mice was studied. Phenotypic analysis of large intestine lamina propria lymphocytes revealed a large increase in memory CD4+ T cells (CD44high, CD45RBlow, CD62Llow). Furthermore, expression of the mucosal homing receptor integrin beta7 was increased on mucosal, but not systemic, CD4+ T cells. Analysis of cytokine production revealed a marked increase in proinflammatory Th1-type cytokines in inflamed colons, as compared with wild-type mice or G(alpha)i2-deficient mice without colitis. Thus, IFN-gamma and IL-1beta levels were increased 13-fold and 30-fold, respectively, with more modest increases in IL-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G(alpha)i2-deficient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G(alpha)i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysis to result from local production within the lamina propria.
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PMID:G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines. 901 44

Experimental data indicate that mucosal CD4+ T cells play an important role in the pathogenesis of inflammatory bowel disease (IBD). Based on the pattern of cytokine production, CD4+ T cells may be distinguished into two different phenotypes. Th1 responses are characterized by secretion of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, lymphotoxin, and interferon (IFN)-gamma and are associated with delayed-type hypersensitivity reactions, whereas Th2 responses, which are characterized by secretion of IL-4, IL-5, and IL-10, have been associated with humoral immune responses and allergy. To assess the number of IFN-alpha and IL-4 positive cells in IBD and normal intestinal specimens, frozen sections from intestinal specimens from 10 Crohn's disease (CD), 8 ulcerative colitis (UC), and 8 healthy controls were examined by immunohistochemistry. Monoclonal antibodies for CD3, CD8, IFN-gamma, and IL-4 were used. T-lymphocyte infiltration and cytokine expression by epithelial, lamina propria, and submucosal cells were scored on a four-point scale by two independent observers who were blinded for the clinical data. One-way analysis of variance (ANOVA) testing was used for statistical analysis. In intestinal specimens from IBD patients, the number of CD3+ cells was found increased in the lamina propria and, within the submucosa, this increase was significant (p < 0.001). In CD the number of lamina propria IFN-gamma positive cells was significantly increased as compared with controls (p < 0.002). In UC the number of both IFN-gamma and IL-4 producing cells in the lamina propria was not significantly increased as compared with controls. The present results confirm the existence of a Th1-biased pattern production in CD but not in UC.
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PMID:Altered expression of interferon-gamma and interleukin-4 in inflammatory bowel disease. 983 81

To investigate the potential involvement of T helper (Th)2-type responses in murine models of intestinal inflammation, we used trinitrobenzene sulfonic acid (TNBS)-hapten to induce inflammatory bowel disease in situations where Th1-type responses with interferon (IFN)-gamma synthesis are either diminished or do not occur. Intracolonic administration of TNBS to either normal (IFN-gamma+/+) or Th1-deficient IFN-gamma knockout (IFN-gamma-/-) BALB/c mice resulted in significant colitis. In IFN-gamma-/- mice, crypt inflammation was more severe than in IFN-gamma+/+ mice and was accompanied by hypertrophy of colonic patches with a lymphoepithelium containing M cells and distinct B and T cell zones resembling Peyer's patches. Hapten-specific, colonic patch T cells from both mouse groups exhibited a Th2 phenotype with interleukin (IL)-4 and IL-5 production. TNBS colitis in normal mice treated with anti-IL-4 antibodies or in IL-4(-/-) mice was less severe than in either IFN-gamma+/+ or IFN-gamma-/- mice. Our findings now show that the Th2-type responses in TNBS colitis are associated with colonic patch enlargement and inflammation of the mucosal layer and may represent a model for ulcerative colitis.
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PMID:Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses. 1020 35

We analyzed the phenotype, proliferative responsiveness, cytokine production and apoptosis susceptibility of lamina propria lymphocytes to different activation pathways. Lamina propria lymphocytes is a population enriched of activated lymphocytes showing a "memory" phenotype. As opposite to peripheral blood lymphocytes, lamina propria lymphocytes show proliferative hyporesponsiveness when stimulated via TCR/CD3 pathway while proliferative response to the CD2 activation pathway is relatively preserved. Under the latter activation pathway, cytokine production, especially IL-4 and IFN-gamma, is higher than that observed in peripheral lymphocytes. When compared to controls, lamina propria lymphocytes isolated from inflammatory bowel disease (Crohn's disease and ulcerative colitis) show distinctive variation in the cytokine production. In particular, Crohn's disease is characterized by an increased production of IFN-gamma, while in ulcerative colitis an increased production of IL-5 is observable. Among the different regulatory mechanisms contributing to maintain immunological homeostasis we analyzed the susceptibility to apoptosis of lamina propria lymphocytes. We found that CD2-activation pathway is regulated by Fas-mediated apoptosis, which regulates proliferation and cytokine production. In inflammatory bowel disease this apoptosis is defective thus contributing to the chronic inflammation and cytokine dysregulation.
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PMID:[Functional status of intestinal t lymphocytes, regulatory mechanisms, and their variations in the course of Crohn disease and ulcerative colitis]. 1064 62

German shepherd dogs (GSD) are predisposed to enteropathies such as inflammatory bowel disease (IBD) and small intestinal bacterial overgrowth (SIBO). The present study examined the role of cytokines in the immunopathogenesis of both conditions. Duodenal mucosal biopsies were taken from GSDs with small intestinal enteropathies (group 1; N = 16) or control dogs (group 2, N = 12). IL-2, IL-4, IL-5, IL-10, IL-12p40, IFN-gamma, TNF-alpha, and TGF-beta1 mRNA expression was determined by semiquantitative reverse transcriptase polymerase chain reaction. IL-2, IL-5, IL-12p40, TNF-alpha, and TGF-beta1 mRNA expression in group 1 dogs was significantly greater than in group 2 dogs (all P<0.01), but there were no significant differences between dogs with IBD or SIBO. Further, antibiotic treatment in five dogs with SIBO, resulted in reduced TNF-alpha and TGF-beta1 mRNA expression (P<0.05). Such alterations in cytokine mRNA expression suggest heightened immune responses within the duodenal mucosa in GSDs with either SIBO or IBD.
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PMID:Cytokine mRNA expression in mucosal biopsies from German shepherd dogs with small intestinal enteropathies. 1069 6


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