UMLS:C0009319 - FACTA Search

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Query: UMLS:C0009319 (colitis)
19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-10-deficient (IL-10(-/-)) mice develop chronic enterocolitis mediated by CD4+ Th1 cells producing IFN-gamma. Because IL-12 can promote Th1 development and IFN-gamma production, the ability of neutralizing anti-IL-12 mAb to modulate colitis in IL-10(-/-) mice was investigated. Anti-IL-12 mAb treatment completely prevented disease development in young IL-10(-/-) mice. Treatment of adult mice resulted in significant amelioration of established disease accompanied by reduced numbers of mesenteric lymph node and colonic CD4+ T cells and of mesenteric lymph node T cells spontaneously producing IFN-gamma. In contrast, anti-IFN-gamma mAb had minimal effect on disease reversal, despite a significant preventative effect in young mice. These findings suggested that IL-12 sustains colitis by supporting the expansion of differentiated Th1 cells that mediate disease independently of their IFN-gamma production. This conclusion was supported by the finding that anti-IL-12 mAb greatly diminished the ability of a limited number of CD4+ T cells expressing high levels of CD45RB from diseased IL-10(-/-) mice to expand and cause colitis in recombination-activating gene-2(-/-) recipients, while anti-IFN-gamma mAb had no effect. Furthermore, IL-12 could support pathogenic IL-10(-/-) T cells stimulated in vitro in the absence of IL-2. While these studies show that IL-12 plays an important role in sustaining activated Th1 cells during the chronic phase of disease, the inability of anti-IL-12 mAb to abolish established colitis or completely prevent disease transfer by Thl cells suggests that additional factors contribute to disease maintenance.
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PMID:IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. 974 82

Previous studies have shown that the chronic inflammation observed in the colon of IL-10-deficient (IL-10(-/-)) mice is mediated by CD4+ Th1 T cells and is dependent on the presence of IFN-gamma for its initial development. As CD4+ T cells from IL-10(-/-) mice will cause colitis when transferred into recombinase-activating gene (Rag)-deficient recipients, we considered the possibility that the recipients' NK cells could be an important source of IFN-gamma for the development of colitis. Therefore, the ability of IL-10(-/-) CD4+ T cells to cause colitis in Rag-deficient recipients that had been depleted of NK cells was tested. Contrary to our expectations, NK cell-depleted recipients of IL-10(-/-) CD4+ T cells developed accelerated disease compared with nondepleted recipients. Furthermore, CD4+ T cells from normal mice (IL-10(+/+)) also caused colitis in NK cell-depleted recipient mice, but not in nondepleted recipients. NK cells inhibited effector CD4+CD45RBhigh T cells, and subsequent experiments showed that this effect was dependent on perforin. Thus NK cells can play an important role in down-regulating Thl-mediated colitis by controlling the responses of effector T cells to gut bacteria.
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PMID:A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. 975 40

IL-7 is a stromal cell-derived cytokine with a well-established physiologic role in lymphocyte biology. This report describes an unexpected role for IL-7 in the development of colitis in a T and B cell-deficient environment. Recombination-activating gene-2 (RAG-2)-deficient mice (RAG-2(-/-)) were exposed to and subsequently maintained a horizontally transmitted microbial flora that included Helicobacter hepaticus. These animals mounted a strong myeloid cell response and developed both systemic and local signs of a severe colitis. A striking infiltration of F4/80 and MHC class II-positive cells was seen in the colon and cecum of animals undergoing the disease. Mice mutant for both IL-7 and RAG-2 (IL-7/RAG-2(-/-)) that were colonized by the same flora showed no signs of myeloid responses or colitis, indicating that IL-7 plays a critical role in exacerbating a non-T cell/non-B cell-mediated chronic inflammatory response. Recombinant IL-10 protein therapy was able to prevent the occurrence of colitis in susceptible mice, suggesting a pivotal role for macrophages. The implications of a role for IL-7 in this disease model with respect to human inflammatory bowel disease are discussed.
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PMID:IL-7 deficiency prevents development of a non-T cell non-B cell-mediated colitis. 982 May 48

In this review, I hope to have highlighted that cytokines are of crucial importance in the normal homeostasis of the gut immune system, the interactions of the gut immune system with enteric antigens and also in tissue injury associated with IBD. There is evidence from a number of different systems that the response to nominal non-replicating antigens, administered nasally or orally, is skewed towards a non-Th1 type of response. To say that the response is Th2, Th3 or Tr is premature. IL-10 and TGF beta seem to be important in downregulating potentially tissue-damaging Th1 responses to the normal flora and possibly food antigens. However, it need to be seen whether the mouse results also apply to humans. A consistent pattern in disease states, whether it be human or mouse, is an exaggerated Th1 type response with excess local production of IFN-gamma and TNF alpha, and its association with tissue injury. An important question to address is whether this represents a switch from the Th2, Th3, or Tr pathway towards a Th1 pathway, or whether the Th1 pathway is in fact always present in the gut, but is kept in check and non-pathogenic by regulatory cells. Equally important is the need to discover where regulation occurs: is it in the PP or the lamina propria? Intriguing results from Kronenberg and colleagues have shown that SCID mice reconstituted with CD45RBhi or CD45RBlo cells show no difference in the re-population of the gut prior to disease (ARANDA et al. 1997). The reason for colitis developing in those mice reconstituted with CD45RBhi cells is therefore more complex than merely differential re-population kinetics. No matter what the outcome is, these and other related questions dealing with the induction and expression of mucosal T-cell responses are going to produce some surprises in the next few years.
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PMID:Effector and regulatory lymphoid cells and cytokines in mucosal sites. 989 58

IL-10 plays an important role in preventing excessive inflammation to the normal flora in the intestinal lumen. The purpose of this study was to compare the effect of normal flora on inflammation in mice in which the IL-10 gene was disrupted. IL-10 knock-out mice housed in germfree conditions remained healthy while those housed in conventional conditions developed colitis after weaning, suggesting that IL-10 inhibits the adverse responses to luminal Ag. Crypt abscesses were present in virtually all of the diseased animals as evidenced by flattening of the epithelial cells and a large number of neutrophils in the lumen of the crypt. Since KC is a chemokine that is capable of recruiting neutrophils in mice, mRNA and protein for KC was measured. Increased levels of both KC mRNA and protein were detected in the colon of diseased mice. To determine whether the epithelial cells were capable of synthesizing KC and contributing to neutrophil accumulation in the crypts, a murine intestinal epithelial cell line (Mode-K) was shown to express mRNA and protein for KC. Two cytokines induced in association with colitis in these mice, TNF-alpha and IFN-gamma, increased the expression of KC mRNA and protein in murine epithelial cells. However, IL-10 was incapable of decreasing the induction of KC, even though the cells expressed the IL-10 receptor. These results suggest that the neutrophil chemokine KC is produced by gastrointestinal epithelial cells in response to inflammatory mediators that are expressed following exposure to normal flora in animals lacking IL-10.
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PMID:Expression of the neutrophil chemokine KC in the colon of mice with enterocolitis and by intestinal epithelial cell lines: effects of flora and proinflammatory cytokines. 997 4

We have described recently that TNBS-induced colitis, an animal model of chronic inflammatory bowel disease (IBD), can be cured by treatment with anti-CD44v7. This finding led us to evaluate whether CD44v7 may be of functional importance in patients with IBD. Expression of CD44 variant isoforms (CD44v) has been evaluated on PBMC of 46 patients with IBD, 43 patients with autoimmune diseases not affecting the gastrointestinal tract, 26 patients with nonautoimmune disease, and 24 healthy donors. In all groups, expression of CD44v on freshly harvested PBMC was not above or was borderline above background levels. After in vitro stimulation, expression of CD44 standard (CD44s) and CD44v6 was strongly up-regulated. Exclusively on PBMC of patients with autoimmune disease, high expression of CD44v3 and CD44v7 was observed. CD44v3 and CD44v7 were mainly expressed on subsets of CD4+ lymphocytes, B cells, and monocytes; CD44v6 was predominantly detected on CD4+ and CD8+ cells. Considering functional activity, CD44v7 apparently exerted a dual effect. After culturing PBMC in the presence of anti-CD44v7, a higher percentage of cells produced IL-10. This was irrespective of whether the PBMC were derived from healthy donors or from patients with autoimmune disease or IBD. On the other hand, PBMC of all donors proliferated upon cross-linking of CD3 and CD44s or CD3 and CD44v6. Instead, costimulatory activity of CD44v7 was seen only in PBMC of patients with autoimmune disease and IBD. Because expression and function of CD44v7 in patients with systemic autoimmune disease and IBD have been much like the ones in mice suffering of TNBS-induced colitis, it is tempting to speculate that blockade of CD44v7 could also be of therapeutic relevance in the human diseases.
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PMID:CD44 variant isoforms on blood leukocytes in chronic inflammatory bowel disease and other systemic autoimmune diseases. 1037 17

IL-12 modulates Th1 immune response during chronic colitis. Mechanisms regulating IL-12 synthesis in human intestine are poorly understood. The aim of this study was to investigate the effect of IFN-gamma and PGE2 on lipopolysaccharide (LPS)-stimulated LPMC IL-12 production. Normal LPMC cultures were run in the presence or absence of IFN-gamma and/or PGE2 before LPS stimulation. To examine the role of endogenous PGE2 on LPS-stimulated IL-12 release, LPMC cultures were added of indomethacin before LPS stimulation. IL-12, IL-10 and IL-8 were measured by ELISA. No IL-12 was detected in either unstimulated or LPS-stimulated LPMC cultures. In contrast, LPMC released IL-8 (650 +/- 125 pg/ml) and IL-10 (75 +/- 25 pg/ml) in response to LPS. Treatment of LPMC with IFN-gamma facilitated LPS-stimulated IL-12, whereas it completely abrogated IL-10 production. IL-12 release by LPMC stimulated with IFN-gamma and LPS was significantly inhibited by exogenous IL-10. The addition of PGE2 to IFN-gamma-treated LPMC cultures inhibited in a dose-dependent manner LPS-induced IL-12 secretion. Furthermore, IL-12 was detectable (85 +/- 25 pg/ml) in the supernatants of LPMC cultures treated with indomethacin and LPS. In contrast to the effect on IL-12, PGE2 significantly augmented LPS-stimulated LPMC IL-10 production. However, the inhibition of IL-12 by PGE2 was only partially reversed by anti-IL-10. In a simplified model of LPS tolerance, we finally showed that monocyte-derived macrophages exhibited reduced IL-12 production after repeat LPS stimulation. In these cell cultures, indomethacin abrogated the induction of LPS desensitization. IFN-gamma and PGE2 modulate differently the LPMC responsiveness to LPS in terms of IL-12 synthesis.
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PMID:Interferon-gamma (IFN-gamma) and prostaglandin E2 (PGE2) regulate differently IL-12 production in human intestinal lamina propria mononuclear cells (LPMC). 1046 49

A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.
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PMID:An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. 1051 89

With recent elucidation of pathophysiology and inflammatory process on inflammatory bowel disease(IBD), new drugs and treatments for IBD have developed rapidly. In addition to it, mechanisms of salicylazosulfapyridine, 5-aminosalicylic acid, and glucocorticoid have been clarified at molecular levels as cell transcription factors of NF-kappa B. This paper described the following recent therapy performed in IBD patients; 1)leukocytapheresis by G-column, LCAP and centrifugal separator. 2)cytokine and anti-cytokine therapy with anti-TNF-alpha chimeric monoclonal antibody and IL-10 for treatment of Crohn' disease. 3)therapy with antisense oligonucleotide against ICAM-1 in Crohn's disease, and against p65 subunit of NF-kappa B in TNBS induced colitis in mice. 4)therapy modulating receptor function of target cells. 5)therapy with antibody against cell adhesion molecules. 6)radical scavenger therapy with lipo-SOD. And, 7)treatment with low molecular heparin.
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PMID:[Present states of development in new drugs and treatment of inflammatory bowel disease]. 1057 18

We have described recently that anti-CD44s, anti-CD44v6 and anti-CD44v7 interfere with delayed-type hypersensitivity (DTH) reactions. Yet, TNBS-induced colitis can be cured only by anti-CD44v7. To clarify the mechanisms underlying the divergent functional activities of CD44v6 and CD44v7 we explored their contribution to lymphocyte activation in vivo and in vitro. CD44v6 and CD44v7 are distinctly expressed on subpopulations of activated lymphocytes. Expression of CD44v6 is mainly restricted to T cell blasts. CD44v7 has been detected on CD4(+) cells, B cells and monocytes. Mitogenic and antigenic stimulation of lymphocytes in vitro was impaired in the presence of anti-CD44v6 and anti-CD44v7. Accordingly, anti-CD44v6 and anti-CD44v7 mitigated the DTH reaction in 2,4-dinitro-1-fluorobenzene-sensitized and challenged mice. However, the seemingly similar effects of CD44v6- and CD44v7-specific antibodies resulted from different activities. Anti-CD44v6 treatment led to a down-regulation of IL-2 and IFN-gamma production predominantly by CD8(+) cells. In anti-CD44v7-treated mice expression of IL-12 was decreased. Elevated levels of IL-10 accompanied this reduction. The latter resulted from an anti-CD44v7-mediated blockade of interactions between CD4(+) cells and monocytes as well as an active triggering of B cells. Thus, anti-CD44v6 and anti-CD44v7 interfere with lymphocyte activation at very specific points. CD44v6 functions predominantly at the T cell level. CD44v7 influences production of proinflammatory cytokines by B cells as well as an interaction between CD4(+) cells and antigen-presenting cells. As CD44 isoforms do not differ in their intracytoplasmatic tail, the distinct activities must result from expression on different leukocyte subsets and interactions with distinct ligands.
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PMID:The CD44 variant isoforms CD44v6 and CD44v7 are expressed by distinct leukocyte subpopulations and exert non-overlapping functional activities. 1060 48

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