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)

The study of production of and response to various soluble mediators by gut-derived mucosal mononuclear cells has contributed significantly to a better understanding of the regulation of the intestinal immune system. So far, a number of factors have been investigated in some detail or in a preliminary fashion: interleukin 1, interleukin 2, interleukin 4, interferon gamma and colony-stimulatory factors. Their level of activity, and their effect on the intestinal mucosal immune system are discussed, particularly in regard to their potential role in the pathogenesis of inflammatory bowel disease.
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PMID:Lymphokines and the intestinal immune response. Role in inflammatory bowel disease. 249 38

Cytokines serve a central function as key factors in the regulation of the intestinal immune response and mediation of tissue damage in inflammatory bowel disease (IBD). Abnormalities in the expression of immunoregulatory cytokines such as IL-2, IL-4, IL-10 and interferon-gamma (IFN-gamma) may indicate a dysregulation of intestinal immunity probably associated with pathogenic events. Therefore, cytokine mRNA concentrations were determined in the mucosa of patients with IBD at sites of active (n = 13) and inactive (n = 12) ulcerative colitis (UC), active (n = 11) and inactive (n = 11) Crohn's disease (CD) and in control patients (n = 14) using quantitative RT-PCR. IL-10 mRNA concentrations were significantly increased in patients with both active UC (P < 0.001) and active CD (P < 0.005) compared with control patients. IFN-gamma mRNA concentrations were also significantly increased both in patients with active UC (P < 0.02) and active CD (P < 0.05) compared with control patients, whereas IL-2 mRNA levels were significantly (P < 0.02) increased only in active CD. IL-4 mRNA expression in the intestinal mucosa was frequently below the detection limit. Our results demonstrate that chronic intestinal inflammation in patients with CD is characterized by an increase of Th1-like cytokines. Furthermore, the increased IL-10 mRNA expression at sites of active IBD suggests that IL-10 is an important regulatory component involved in the control of the inflammatory response in inflammatory bowel disease.
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PMID:Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). 766 89

Although a disturbed immune response to constituents of the gut mucosa has been implicated in the pathogenesis of inflammatory bowel disease, the mechanisms are still unclear. Intestinal T-cells derived from gut biopsies were propagated in vitro as single and co-cultures under different experimental conditions prior to flow cytometry. Intestinal T-cell lines from inflamed mucosa (n = 69) showed a significant (P < 0.001) decrease in CD4+ T-cells compared to T-cells from normal (n = 49) and uninflamed (n = 29) tissue specimens. Co-culturing of inflamed and uninflamed mucosa led to a normalization of CD4+ T-cells in cultures derived from inflamed mucosa. Analysis of supernatants revealed a significantly (P < 0.001) increased secretion of IL-4 under co-culture conditions. Moreover, stimulation of cultures derived from inflamed mucosa with rIL-4 led to a significant (P < 0.001) increase in CD4+ T-cells, whereas anti-IL-4 antibodies or IFN-gamma supplementation of T-cells derived from uninflamed mucosa significantly (P < 0.001) reduced the CD4+ subset. Treatment with IFN-gamma and anti-IL-4 antibodies did not affect the phenotype of T-cells derived from inflamed mucosa. These data suggest that IL-4 might play a key role in the intestinal immune response. Furthermore, this in vitro system allows the investigation of mucosal immune mechanisms in more detail under standardized conditions.
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PMID:Phenotypic and immunoregulatory analysis of intestinal T-cells in patients with inflammatory bowel disease: evaluation of an in vitro model. 778 61

Normal colonic epithelial cells play an important part in the mucosal immune system and use butyrate, a bacterial fermentation product, as an important energy source. Butyrate deficiency has been associated with inflammatory bowel disease, diversion colitis, and pseudomembranous colitis. Butyrate effects on important molecules for epithelial immune functions were studied in a colonic epithelial cell line (HT-29): the constitutive and cytokine regulated expression of secretory component (poly-Ig receptor), HLA class I and II molecules, and intercellular adhesion molecule-1 (ICAM-1). Butyrate facilitated the constitutive expression of secretory component and HLA class I. Butyrate furthermore tended to enhance cytokine mediated stimulation of protein expression, although tumour necrosis factor alpha (TNF) and interleukin 4 (IL 4) responses on HLA class I and secretory component, respectively, were relatively inhibited by butyrate. Cytokine mediated accumulation in the various mRNAs usually increased even more in the presence of butyrate, with the exception of TNF response on HLA class I and secretory component mRNA concentrations. In conclusion, butyrate may substantially influence constitutive and cytokine mediated expression of molecules with immune functions in a complex and differentiated manner, and butyrate deficiencies, as seen in various clinical conditions, might influence mucosal immune responses.
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PMID:Constitutive and cytokine induced expression of HLA molecules, secretory component, and intercellular adhesion molecule-1 is modulated by butyrate in the colonic epithelial cell line HT-29. 779 24

Cytokines produced by intestinal epithelial cells may function as signals to neighbouring immune and inflammatory cells. We investigated production of the neutrophil and T-lymphocyte chemotactic cytokine interleukin-8 (IL-8) by intestinal epithelial cells using four colonic adenocarcinoma cell lines, T84, CaCo-2, HT29 and SW620, as a model system. These cell lines secreted substantial amounts of IL-8 if stimulated with IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma), except CaCo-2 cells, which responded only to IL-1 beta. Bacterial lipopolysaccharide (LPS) was also an efficient stimulus of IL-8 release in SW620 and HT29 cells, whereas T84 and CaCo-2 cells were completely unresponsive to LPS, IL-8 secretion was greater at 4 hr after stimulation and was accompanied by induction of IL-8 messenger RNA. In T84 cells IFN-gamma and epidermal growth factor (EGF) stimulated IL-8 secretion synergistically with TNF-alpha, whereas in SW620 cells this synergism occurred only between IFN-gamma and TNF-alpha. IL-4, IL-10 and transforming growth factor-beta (TGF-beta), which can down-regulate IL-8 production in macrophages, had no effect on IL-8 generation by our cell lines. Adenocarcinoma cell culture supernatants also induced rapid transients of intracellular calcium in neutrophils. Depending on cell line and stimulus, supernatant bioactivity was completely or partially abrogated by neutralizing antibodies to IL-8, indicating that the cell lines investigated also generate other neutrophil-activating factors. IL-8 and possibly other chemokines generated by colonic adenocarcinomas may help to attract tumour-infiltrating leucocytes. Possibly, normal intestinal epithelial cells also have the potential to secrete this potent chemoattractant and thus might contribute to inflammatory responses of the intestinal mucosa, for example in inflammatory bowel disease.
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PMID:Colonic epithelial cell lines as a source of interleukin-8: stimulation by inflammatory cytokines and bacterial lipopolysaccharide. 783 10

Interleukin 2 (IL-2)-deficient (IL-2-/-) mice develop hemolytic anemia and chronic inflammatory bowel disease. Importantly, the induction of disease in IL-2-deficient mice is critically dependent on CD4+ T cells. We have studied the requirements of T cells from IL-2-deficient mice for costimulation with B7 antigens. Stable B7-1 or B7-2 chinese hamster ovary (CHO) cell transfectants could synergize with anti-CD3 monoclonal antibody (mAb) to induce the proliferation of CD4+ T cells from IL-2-/- mutant mice. Further mechanistic studies established that B7-induced activation resulted in surface expression of the alpha chain of the IL-2 receptor. B7-induced proliferation occurred independently of IL-4 and was largely independent of the common gamma chain of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Finally, anti-B7-2 but not anti-B7-1 mAb was able to inhibit the activation of IL-2-/- T cells induced by anti-CD3 mAb in the presence of syngeneic antigen-presenting cells. The results of our experiments indicate that IL-2-/- CD4+ T cells remain responsive to B7 stimulation and raise the possibility that B7 antagonists have a role in the prevention/treatment of inflammatory bowel disease.
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PMID:Activation of CD4+ T lymphocytes form interleukin 2-deficient mice by costimulatory B7 molecules. 861 Jan 40

Spontaneous inflammatory bowel disease (IBD) resembling human ulcerative colitis develops in mice mutant for the T cell receptor alpha gene (TCR-alpha-/-). TCR-alpha-/- mice lack TCR-alpha/beta+ cells but contain TCR-gamma/delta+ cells and a small population of a unique CD4+, TCR-alpha-/beta+(low) cells. Since all the immunoglobulin (Ig) classes are present in these mice, help to B cells must be provided by cells other than TCR-alpha/beta+ cells. In the present study, we found serum levels of IgG1 and IgG2 to be markedly increased in TCR-alpha-/- mice with IBD as compared to TCR-alpha-/- mice without IBD or TCR-alpha+/- controls. An increase in IgG1-, IgG2a- and IgA- but not IgM-secreting mesenteric lymph node (MLN) B cells was detected in TCR-alpha-/- mutant mice. There was also a marked increase in MLN B cells secreting autoantibody (IgG) to tropomyosin, a cytoskeletal protein. Examination of the hyperplastic MLN showed a marked increase in the number of B, TCR-delta+, and CD4+ TCR-alpha-/beta+ cells, similar to the cell population observed at the site of colonic inflammation. Analysis of spontaneous cytokine production by MLN cells using an enzyme-linked immunospot assay, immunohistochemistry, and reverse transcription/polymerase chain reaction showed a decrease of interleukin 2 (IL-2) but a marked increase of IL-4 and interferon gamma (IFN-gamma) production in TCR-alpha-/- mice with IBD as compared to TCR-alpha-/- mice without IBD and TCR alpha+/- control mice. Both TCR-alpha-/beta+ and TCR-delta+ cells were found to be capable of producing IL-4; IFN-gamma was produced mostly by non-T cells, many of which were shown to be CD3- NK 1.1+ cells. We propose that the cytokine imbalance present in these mice results in expansion of B cells, production and switching of autoantibodies to IgG2 subclass, and development of IBD. It is possible that the unusual CD4+ TCR-alpha-/beta+ population and expanded TCR-gamma/delta+ population present in TCR-alpha-/- mice plays a central role in this abnormal immune response.
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PMID:Cytokine imbalance and autoantibody production in T cell receptor-alpha mutant mice with inflammatory bowel disease. 864 89

In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease.
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PMID:Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance. 867 81

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.
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PMID:A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. 867 88

Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.
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PMID:T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. 869 Nov 38


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