Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have described a murine model of IBD that was induced in C.B-17 scid mice by transfer of the CD45RBhi subpopulation of CD4+ T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RBlo CD4+ T cell subset. Here we have dissected the mechanism of pathogenesis of IBD in this model and used this information for rational immunotherapy of the disease. CD4+ cells from diseased mice displayed a highly polarized Th1 pattern of cytokine synthesis upon polyclonal stimulation in vitro. The administration of anti-IFN gamma MAb to mice soon after T cell transfer prevented development of colitis for up to 12 weeks. Continual neutralization of TNF with anti-TNF MAbs reduced the incidence of severe disease; however, neutralization of TNF during only the first 3-4 weeks had no effect. Severe colitis was completely abrogated in mice treated systemically with rIL-10, but not with rIL-4.
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PMID:Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. 760 Feb 84

To clarify the mechanisms of action of immunoglobulin (IgG) in intravenous immunoglobulin therapy for the ulcerative colitis (UC) patients, we studied the therapeutic effect of IgG on experimental rat colitis induced by dextran sulfate sodium and on the production of inflammatory cytokines such as TNF alpha, IL-1 alpha and IL-8. The administration of rat IgG demonstrated to suppress the development of blood stool and the induction of the ulcerative lesion in large intestine. The levels of TNF alpha, IL-1 alpha and IL-8 were increased in blood and mucosa of the large intestine in this model. Rat IgG showed a tendency to decrease the levels of the cytokines in colonic mucosa. This result seems to provide a piece of explanation of how massive administration of IgG shows an improvement in the ulcerative lesion of UC patients.
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PMID:[Effect of gamma-immunoglobulin in experimental colitis induced by dextran sulfate]. 796 29

To clarify the mechanism of action of immunoglobulin (IgG) in intravenous immunoglobulin therapy for ulcerative colitis (UC) patients, we studied the effect of IgG on the dynamics of immunocompetent cells in the colonic mucosa of experimental colitis induced by dextran sulfate sodium (DSS) in rats. The administration of the same species' IgG suppressed the mucosal infiltration of immunocompetent cells (activated T cells, macrophages and neutrophils), although the different species' IgG didn't. We have already shown that the same species' IgG, suppressed the production of inflammatory cytokines (TNF alpha, IL-1 alpha and IL-8) in the colonic mucosa of experimental colitis induced by DSS. In the present report, we demonstrated the different species' IgG, as well as same species' IgG, suppressed the production of inflammatory cytokines (TNF alpha and IL-1 alpha) from lamina propria mononuclear cells of rat large intestine in vitro. Therefore, it was considered that the suppression of cytokine production was a consequence of the decreased immunocompetent cells in colitis mucosa. Furthermore, we demonstrated that the DSS-treated antigen presenting cells (APCs) activated antigen-specific T cells as a possible mechanism underlying the colitis induced by DSS and the same species' IgG inhibited this activation of T cells.
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PMID:[Immunological effect of immunoglobulin on experimental colitis induced by dextran sulfate]. 855 75

The effects of the Lps gene on the development of experimental ulcerative colitis were studied in two genetically different mouse strains: C57B1 and C3H. Acute colitis was induced by adding 3% dextran sulfate sodium (DSS) to the drinking water for a 7-day (C57B1 and C3H) or a 10-day (C57B1) experimental period. Although the DSS treatment initiated the same type of morphological changes in the colon in all groups of mice, an earlier onset and persistent intestinal bleeding occurred in the Lpsn mice (sensitive to lipopolysaccharide, LPS) in comparison with the Lpsd mice (hyporesponsive to LPS). Rectal bleeding appeared on day 7 in 90% of the Lpsn compared to 13% of the Lpsd mice (p < 0.0001). In C57B1 mice, followed for three additional days, 50% of the Lpsn mice died and the surviving animals showed as well as rectal bleeding a large number of Gram-negative bacteria in the liver and spleen. In contrast, the Lpsd mice of the C57B1 strain appeared unaffected by the treatment, although a transient rectal bleeding occurred in 90% on day 8. Also, significantly fewer Gram-negative bacteria were found in the liver and spleen. Even though significantly increased serum endotoxin levels were seen in all DSS-treated groups compared to controls on day 7, the serum levels of TNF alpha were significantly increased only in the Lpsn mice. In DSS-induced colitis the Lpsn genotype conferred on the mice an increased LPS susceptibility, resulting in an augmentation of the inflammatory response to Gram-negative bacteria and their endotoxins. The results suggest that LPS-induced host effector mechanisms significantly enhanced the intestinal bleeding, systemic inflammatory response, and mortality in mice with DSS-induced colitis. In addition, the host defense against the invading and systemically spread bacteria most probably involved additional genes.
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PMID:The role of the Lps gene in experimental ulcerative colitis in mice. 898 46

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

The cytokines TNF and IL-1 have been implicated as mediators of the inflammatory processes in patients with inflammatory bowel disease (IBD). To investigate the role of these cytokines in mucosal inflammation we used anti-cytokine strategies in a mouse model of acute and chronic colitis. Mice which received 5% dextran sulphate sodium (DSS) in their drinking water showed signs of acute colitis on day 4, with severe weight loss and bloody diarrhoea. Chronic colitis was established after four cycles of feeding 5% DSS for 7 days and water for 10 days, with the mice showing diarrhoea but no weight loss. In acute colitis, treatment with anti-IL-1 reagents, anti-TNF MoAb, or dexamethasone (DEX) led to aggravation. By contrast, in chronic colitis, treatment of mice with several IL-1 activity-inhibiting reagents failed to show significant effects, whereas anti-TNF MoAb or DEX significantly reduced the colitis. We conclude that in acute colitis IL-1 and TNF are beneficial, whereas in chronic colitis, TNF but not IL-1 seems to play a major role in perpetuation of chronic inflammation.
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PMID:Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. 903 Aug 75

Chronic colitis develops spontaneously in mice mutant for T-cell receptor alpha (TCR alpha) genes maintained in pathogen-free conditions. Our previous studies indicate that the cytokine imbalance caused by a lack of TCR alpha beta + T cells may be associated with the development of chronic colitis in TCR alpha-mutant (TCR alpha -/-) mice. The histologic changes of chronic colitis are recognizable by 3 to 4 months of age and are characterized by marked crypt cell hyperplasia and the presence of an inflammatory cell infiltrate. Because early events in the development of chronic colitis may be important in the pathogenesis of the disorder, we investigated the changes in the colon at a time when chronic colitis was not yet histologically recognizable. In vivo labeling with 5-bromo-2'-deoxyuridine revealed increased epithelial proliferation in the crypts by 6 to 8 weeks of age. There was an increase in number of T cells in the colon of TCR alpha -/- mice compared with that in TCR alpha +/- (heterozygous TCR alpha-mutant) mice after 6 weeks of age. The predominant T-cell subsets were CD4+, TCR alpha- beta +, and TCR gamma delta + cells. Reverse transcription-PCR and immunohistochemistry of the colonic mucosa obtained from TCR alpha -/- mice (> 6 weeks old) showed a marked increase of IL-1 alpha and IL-1 beta but not of TNF alpha or transforming growth factor beta-1 compared with TCR alpha +/- mice. In vivo neutralization of IL-1 alpha or IL-1 beta by specific mAb suppressed colonic epithelial proliferation and decreased colonic mucosal T-cell infiltration in 8-week-old TCR alpha -/- mice. These results provide direct evidence that overproduction of IL-1 alpha and IL-1 beta in the colonic mucosa may play an important role in the early stages of development of chronic colitis in TCR alpha -/- mice.
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PMID:Role of cytokines in the early stages of chronic colitis in TCR alpha-mutant mice. 912 Nov 21

The mechanisms underlying inflammatory bowel disease (IBD) remain obscure but the importance of inflammatory processes is clear and most pharmacological therapies inhibit inflammation. The search for more effective agents with low toxicity continues. To test the possibility that the antiinflammatory/anticytokine peptide alpha-MSH can be used to control IBD, the peptide was administered to a murine colitis model. The peptide treatment had marked salutary effects: it reduced the appearance of fecal blood by over 80%, inhibited weight loss, and prevented disintegration of the general condition of the animals. Mice given alpha-MSH showed markedly lower production of TNF alpha by tissues of the lower colon stimulated with concanavalin A; the inhibitory effect of alpha-MSH on production of inflammatory nitric oxide by lower bowel tissue was even greater. The combined results indicate that alpha-MSH modulates experimental IBD, perhaps by inhibiting production within the gut of the local proinflammatory agents TNF alpha and nitric oxide, or by inhibiting inflammatory processes closely linked to these mediators.
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PMID:alpha-MSH modulates experimental inflammatory bowel disease. 914 24

Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of ulcerative colitis. A 2,4,6-trinitrobenzenesulfonic acid sodium salt (TNBS) colitis model was established to examine the effect of selective iNOS inhibition, by S-(2-aminoethyl) isothiouronium bromide (ITU), on colonic mucosal cell damage and inflammation. Rats, killed 7 days after TNBS, had increased colonic mucosal levels of iNOS and interleukin-8 (IL-8), in addition to severe colonic inflammation which was characterized by significantly increased colon weight, damage score and colonic myeloperoxidase activity (MPO) (a marker of neutrophil influx). TNBS-treated rats had markedly decreased body weight and thymus weight. Administration of colitic rats with ITU significantly inhibited iNOS activity/expression and tended to reduce mucosal levels of IL-8, but no effect on MPO activity was observed. Following ITU therapy, colitic rats had reduced colonic damage and losses in body weight and thymus weight were reversed. Improvement of TNBS colitis by ITU suggested that excess NO, produced by iNOS, may have contributed to the initiation/amplification of colonic disease, by mechanisms including enhancement of IL-8 release. NO-mediated enhancement of pro-inflammatory cytokine release was further investigated in vitro. Lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) stimulated release of nitrite, lactate dehydrogenase (LDH), TNF alpha, IL-1 beta and IL-8 from rat peritoneal macrophages, all of which were significantly reduced by ITU. This suggests that NO-mediated cell damage enhances pro-inflammatory mediator release from macrophages. In addition, enhancement of IL-8 and TNF alpha release was also partially NO-dependent in activated peritoneal neutrophils. Therefore, the amelioration of TNBS colitis by ITU could include inhibition of NO-mediated pro-inflammatory cytokine release.
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PMID:Pathophysiological role of nitric oxide in rat experimental colitis. 966 7

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


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