Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009319 (colitis)
 19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.
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PMID:Antibodies to interleukin 12 abrogate established experimental colitis in mice. 759 99

Interleukin 10 (IL-10) indirectly prevents antigen-specific T-cell activation, which is associated with downregulation of the antigen presentation and accessory cell functions of monocytes, macrophages, Langerhans cells and dendritic cells. In addition, IL-10 inhibits T-cell expansion by directly inhibiting IL-2 production by these cells. These properties of IL-10, together with its capacity to downregulate the production of proinflammatory cytokines and chemokines by activated monocytes, polymorphonuclear leucocytes and eosinophils, indicate that IL-10 is a potent immunosuppressant in vitro. IL-10 has similar activities in vivo. It inhibits lipopolysaccharide or staphylococcal enterotoxin B induced lethal shock in mice. In addition, IL-10 deficient mice develop chronic inflammatory bowel disease, which could be reduced, or prevented by IL-10 treatment. IL-10 also prevented the development of colitis in a SCID mouse model. Collectively, these data indicate that IL-10 has great potential therapeutical utility in the treatment of diseases, such as chronic inflammation, autoimmune diseases, transplant rejection, graft-versus-host disease and sepsis.
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PMID:Immunosuppressive and anti-inflammatory properties of interleukin 10. 854 Oct 28

We investigated the production of proinflammatory cytokines (IL-1 beta, IL-6, IL-8, and TNF-alpha) and immunoregulatory cytokines (IL-2, IFN-gamma, and IL-10) in the colonic mucosa of patients with active ulcerative colitis (UC), inactive UC, and non-inflammatory bowel disease (IBD) colitis by organ culture. The production of proinflammatory cytokines was significantly increased in all the studied groups compared with controls. In active UC, levels of these cytokines, except for IL-1 beta, were markedly increased compared with non-IBD colitis, and the levels were positively correlated with the degree of inflammation. Patients with non-refractory active UC receiving steroids showed levels of IL-1 beta and TNF-beta production similar to those in controls. IL-10 production was also significantly increased in all the studied groups, the value of being the highest in active UC. In contrast, IL-2- and IFN-gamma production was significantly decreased in both active and inactive UC compared with controls, and the values in active UC were inversely correlated with the degree of inflammation. In non-IBD colitis, decreased IL-2 production was observed, but IFN-gamma production did not differ from that in controls. In an experimental study, each of the proinflammatory cytokines was injected into the colonic mucosa of rats. All of these proinflammatory cytokines, except for IL-1 beta induced colonic mucosal damage that showed some histologic features similar to those of UC. These results suggest that the increased production of proinflammatory cytokines, particularly of IL-6 and IL-8, and the decreased production of IL-2- and IFN-gamma, probably downregulated by the enhanced production of IL-10, play an important role in the pathogenesis of UC.
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PMID:The role of proinflammatory and immunoregulatory cytokines in the pathogenesis of ulcerative colitis. 856 92

Gene-targeted mice lacking the IL-2 gene (IL-2 -/- mice) develop various forms of autoimmunity as well as severe colitis, either spontaneously in a conventional environment or after immunization with 2,4,6-trinitrophenol (TNP)-conjugated keyhole limpet hemocyanin (KLH) in a specific pathogen-free environment. We show here that the induction of colitis with TNP-KLH induces a change in the thymocyte population characterized by decreased numbers of double positive (DP; CD4+CD8+) thymocytes (IL-2 +/+, 45.2 x 10(6) vs IL-2 -/-, 23.6 x 10(6)) and increased numbers of single positive (SP; CD4+CD8- or CD4-CD8+) thymocytes (IL-2 +/+, 5.3 x 10(6) vs IL-2 -/-, 20.9 x 10(6)). The latter also bear activation markers. In addition, thymocytes from TNP-KLH-immunized IL-2 -/- mice produce more IFN-gamma and less IL-4 than similarly immunized IL-2 +/+ mice. These defects in thymocyte maturation and lymphokine production are IL-12 driven, since they are prevented when immunized IL-2 -/- mice are coadministered with anti-lL-12. Furthermore, we demonstrate that IL-2 -/- mice exhibit decreased cortical apoptosis as determined by thymocyte numbers and detection of apoptotic cells in situ. Finally, we show that colitis-inducing thymocytes are generated in the immunized IL-2 -/- thymus, since IL-2 +/+ mice develop colitis following injection of small numbers of single positive thymocytes from immunized IL-2 -/- mice but not from IL-2 +/+ mice. Taken together, these data indicate that, in the absence of IL-2, thymocyte maturation is abnormally directed by IL-12 toward the generation of mature, activated Th1-type thymocytes that are capable of mediating colitis.
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PMID:Dysregulated intrathymic development in the IL-2-deficient mouse leads to colitis-inducing thymocytes. 897 80

Gene-targeted mice deficient for IL-2 (IL-2 -/- mice) are free of apparent disease when maintained under germfree conditions but develop colitis and autoimmunity in a conventional environment. Here we show that colitis can be reproducibly induced in IL-2 -/- mice, but not in IL-2 +/+ mice, by i.p. immunization with Ag in CFA; thus enabling the systematic study of the immunopathogenesis of the colitis. We found that TNP-KLH or TNP-OVA had the most significant effect in inducing colitis, and while TNP-KLH immunization leads to the early appearance of activated T cells in the colons of both IL-2 -/- and IL-2 +/+ mice, only lamina propria cells of IL-2 -/- mice produced high amounts of INF-gamma. Moreover, both infiltrating colon CD4+ (69%) and CD8+ (6%) T cells secrete large amounts of IFN-gamma; however, only the depletion of CD4+ T cells leads to abrogation of the inflammation. In further analysis, we showed that the high IFN-gamma production is IL-12 driven, since colonic tissues of IL-2 -/- mice but not IL-2 +/+ mice show the presence of heterodimeric IL-12 and co-administration of anti-IL-12 with TNP-KLH completely prevented colitis and significantly reduced IFN-gamma production. Finally, we demonstrate that IL-2 -/- mice are deficient in their ability to induce Th2 responses after TNP-KLH challenge and that such immunization also leads to autoimmune-like phenomena in other organs of IL-2 -/- mice. These findings suggest that in the absence of IL-2 systemic administration of Ag induces primarily Th1 cells driven by overexpression of heterodimeric IL-12.
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PMID:Induction and prevention of colonic inflammation in IL-2-deficient mice. 899 69

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

Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4(+) CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4(+) CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.
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PMID:Altered immune responses in interleukin 10 transgenic mice. 918 82

One of the major advances in the understanding of inflammatory bowel disease has been the observation that mice with immunoregulatory defects, such as interleukin-2 knockout (IL-2 -/-) mice, develop spontaneous gut inflammation. Here we have characterized the immune response in the ileum, caecum and colon of these mice before and after the onset of colitis by examining the cellular infiltrate, the cytokines produced by these cells and the mucosal vascular addressin MAdCAM-1. IL-2 -/- mice developed colitis after 35 days of age and before this the mice were apparently healthy. IL-2 -/- mice aged over 35 days with colitis had large numbers of CD4+, CD8+, alpha beta T-cell receptor (TCR)+ and gamma delta TCR+ T cells, macrophages, dendritic cells and MAdCAM-1+ endothelial cells in the caecum and colon. This was associated with an increase in the number of interferon-gamma (IFN-gamma), IL-1 and tumour necrosis factor-alpha (TNF-alpha) transcripts and a decrease in IL-4 and IL-10 transcripts. Treatment of IL-2 -/- mice with cyclosporin A significantly delayed mortality. Interestingly, IL-2 -/- mice under 35 days, although healthy, did show some subtle immunological signs of preclinical disease. There was a significant increase in the number of macrophages and dendritic cells in the colonic lamina propria and increased mRNA for IL-1 and TNF-alpha. There were also increased numbers of MAdCAM-1+ endothelial cells, but IFN-gamma transcripts were not elevated. These results suggest that T-cell-mediated colitis in IL-2 -/- mice may be secondary to an initial non-specific inflammation.
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PMID:Characterization of the mucosal cell-mediated immune response in IL-2 knockout mice before and after the onset of colitis. 920 68

Over the past few years, application of targeted gene deletion and transgenic approaches has led to the often unanticipated development of rodent lines which develop inflammatory bowel disease. While none of these lines recapitulate the histopathological and clinical features usually associated with human inflammatory bowel disease (IBD) in their entirety, many exhibit key features comprising the development of "spontaneous" chronic and acute inflammation. These models include targeted deletion of the genes encoding IL-2, IL-10, TGF beta, T-cell receptor alpha/beta, keratin 8, and Gi2 alpha. In addition, animals expressing transgenes for the human WA-B27 (with beta-2 microglobulin) as well as a dominant negative construct which functionally blocks N-cadherin have also been observed to result in chronic inflammatory bowel disease. Most of the mutant murine lines experience a diffuse colitis, but some (HLA-B27 transgenic and IL-10-deficient) also experience small bowel inflammation. The variety of manipulations provides some important broad insights: (1) IBD can result from dysregulation of mucosal immune responses or impairment of epithelial barrier function, and (2) the natural history of inflammation resulting from mutation at a single genetic loci is substantially modulated by other genetic factors. With the rapidly-increasing variety of mutant mice, comparison of the residual components of immune system in lines developing IBD with those of lines not developing IBD, it is possible to deduce a requirement for TCR gamma/delta CD4+ lymphocytes as well as pivotal role of IFN gamma and (as a suppressive factor) IL-10. Study of a number of models has demonstrated the important interaction between environmental factors and genetic predisposition. Thus, in at least some of the lines (IL-2-deficient and HLA-B27) the inflammatory bowel disease is not observed when the mutant mice are maintained in a germ-free environment but does develop after reconstitution with a pathogen-free flora. In the TCR alpha/beta deficient mice, appendectomy in the neonatal period prevents the subsequent development of colitis. In still other models, inflammation may not occur without some challenge by an exogenous external agent, e.g., mice deficient in intestinal trefoil factor (ITF) exposed to dextran sodium sulfate (1). These models offer great promise to permit further dissection of the various constituents of the intestinal epithelium and mucosal immune response systems which are necessary for maintaining normal homeostasis and which can contribute to the development of inflammatory bowel disease. Further, they offer powerful tools for exploring the interaction between genetic and environmental factors to explicate the pathogenesis of inflammatory bowel disease and to develop new therapeutic intervention strategies.
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PMID:Lessons from genetic models of inflammatory bowel disease. 926 Mar 28

A severe, Th1-mediated experimental colitis with similarities to inflammatory bowel disease in humans can be induced by a single injection of 2,4,6-trinitrophenol (TNP)-substituted protein plus adjuvant in IL-2-/- mice. To determine the early events involved in the pathogenesis of IL-2-/-colitis, we compared the function of lamina propria (LP) T cells from IL-2-/- and IL-2+/+ mice subjected to disease-inducing (TNP-conjugated keyhole limpet hemocyanin [TNP-KLH]) and disease-inhibiting (anti-CD3) immunization protocols. We show that LP T cells in TNP-KLH-immunized IL-2-/- mice fail to produce TGF-beta early (day 2), whereas LP T cells in TNP-KLH-immunized IL-2+/+ mice exhibit an approximately eightfold rise in TGF-beta secretion. The critical importance of local TGF-beta production was further substantiated by the following findings. 1) LP T cells from TNP-KLH-immunized IL-2-/- mice administered anti-CD3 (i.p.) exhibit a significant rise in TGF-beta, production but fail to produce IFN-gamma, and such mice do not develop colitis. 2) TNP-KLH-immunized IL-2-/- mice administered anti-CD3 and coadministered anti-TGF-beta mAb again give rise to IFN-gamma-producing LP cells, and such mice develop colitis. 3) TNP-KLH-immunized IL-2+/+ mice administered anti-TGF-beta mAb exhibit pockets of mononuclear cell infiltrates in the LP. These results indicate that the disposition of IL-2-/- mice to develop chronic colonic inflammation is due to a Th1 cell response in the LP that is not appropriately counter-regulated by the production of the suppressor cytokine, TGF-beta.
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PMID:TGF-beta production regulates the development of the 2,4,6-trinitrophenol-conjugated keyhole limpet hemocyanin-induced colonic inflammation in IL-2-deficient mice. 931 62


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