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 local release of inflammatory mediators are intricately linked with initiation and propagation of the inflammatory reaction in ulcerative colitis (UC) and Crohn's disease. We have used immunohistochemical staining of colonic biopsies to determine the cell of origin and the location of the cells which synthesize of TNF-alpha and IL-1 beta in patients with UC and Crohn's colitis. Patients were chosen from children aged 7-16 years, who had UC or Crohn's diagnosed following review of colonic biopsies taken during colonoscopy. The patients reviewed had not received treatment for inflammatory bowel disease. Paraffin embedded colonic biopsies were sectioned, deparaffinized, and stained with mouse monoclonal IgG antibodies directed against human recombinant TNF-alpha and IL-1 beta. The colonic lamina propria of all biopsies from patients with UC or Crohn's colitis was expanded with a mixed mononuclear, polymorphonuclear, lymphocytic, and plasmacytic infiltrate. Mononuclear cells distributed throughout the interstitium, stained prominently for both TNF-alpha and IL-1 beta. Plasmacytes, polymorphonuclear leukocytes, small lymphocytes, and foamy macrophages did not stain for either TNF-alpha or IL-1 beta. Transmigrating mononuclear cells in crypt epithelium also stained brightly for both TNF-alpha and IL-1 beta. Colonic epithelial cells did not stain for either TNF-alpha or IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor and IL-1 beta expression in pediatric patients with inflammatory bowel disease. 849 48

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

Previous work has suggested that the interleukin-1 (IL-1) receptor antagonist, IL-1ra, may regulate mucosal inflammation in inflammatory bowel disease. The present study assessed the relationship of mucosal IL-1ra levels to histologic severity of inflammation and the related proinflammatory cytokines IL-1 beta and IL-6 in children with inflammatory bowel disease. Colonic biopsy specimens from 29 patients with ulcerative colitis, 27 with Crohn's disease, and 24 noninflammatory control subjects were assayed for IL-1ra, IL-1 beta, and IL-6 by enzyme-linked immunosorbent assay. Histologic activity was graded as none, mild, moderate, or severe. Mucosal IL-1 beta levels, but not IL-1ra levels, were significantly elevated in moderate/severely inflamed biopsies from patients with either ulcerative colitis (p < 0.01) or Crohn's disease (p < 0.001) compared with those with none/mild inflammation. The mucosal molar ratio of IL-1ra/IL-1 beta was significantly lower for moderate/severe inflammation compared with none/mild inflammation for patients with ulcerative colitis (p < 0.05) and Crohn's disease (p < 0.01). The mucosal IL-1ra/IL-1 beta ratio was similar in controls to none/mild inflamed biopsies from subjects with either ulcerative colitis or Crohn's disease. Our observations suggest that increasing mucosal inflammation in inflammatory bowel disease in children is associated with a decrease in the "normal" effective IL-1ra/IL-1 beta ratio in which IL-1ra predominates. The importance of this abnormality to the pathogenesis of inflammatory bowel disease awaits further study.
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PMID:Relationship of interleukin-1 receptor antagonist to mucosal inflammation in inflammatory bowel disease. 858 93

Chronic inflammation in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) may be attributed partly to increased secretion of inflammatory cytokines. The aim of this study was to investigate simultaneously the spontaneous release patterns of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1 beta), and interleukin-6 (IL-6) by organ cultures of inflamed mucosa from IBD patients. Organ cultures of involved IBD mucosa spontaneously produced increased amounts of TNF-alpha, IL-1 beta, and IL-6 compared to normal mucosa. The patterns of cytokine release between Crohn's disease and ulcerative colitis organ cultures were not significantly different. Increased inflammatory cytokine production by lamina propria mononuclear cells (LPMCs) and mucosa treated with EDTA suggests that these cytokines originate mainly from LPMCs. These results confirm the role of inflammatory cytokines in IBD and shed a new light on the role of TNF-alpha in IBD.
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PMID:Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease. 873 57

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

Controlled clinical trials have shown that several immunosuppressive drugs are efficacious in patients with inflammatory bowel disease. These drugs each have multiple effects on the immune system and the exact mechanism of their beneficial effect in inflammatory bowel disease is unknown. None of these agents directly inhibits the 'inflammatory cytokines' such as IL-1 beta, IL-6, IL-8, or TNF-alpha. However, they can all inhibit generation of leukocyte precursors in the bone marrow, that is, the cells that produce such cytokines. The effects of current agents on T-cell subsets and their associated cytokines remains unclear. Based on insights from novel mouse models of chronic colitis, the goal of 'immunotherapy' going into the next decade should be either to inhibit specifically the effector T cells mediating disease or to enhance the regulatory T cells that inhibit such effector cells or, ideally, to do both. Therapy meeting this goal, which will need to based on a more thorough understanding of the immunopathogenesis of inflammatory bowel disease, should allow a more specific or 'surgical' approach to immunotherapy and simultaneously reduce its risks and adverse effects.
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PMID:The effects of immunosuppressive agents on cytokines. 889 8

Cytokines and insulin-like growth factors (IGFs) are involved in the induction and/or perpetuation of inflammatory bowel disease. The effect of fasting on inflammatory bowel disease was studied in a mouse experimental model of acute colitis caused by adding dextran sulfate sodium (DSS) to drinking water. Animals were either fed ad libitum or fasted (water only) for 2 days before death. Inflammation and tissue damage, measured as a colitis activity score, were markedly reduced in fasted (2.4 +/- 0.1) compared to fed (5.3 +/- 0.1) DSS animals (P < 0.0001). Colon interleukin-1 beta (IL-1 beta), IGF-I, and tumor necrosis factor-alpha messenger RNAs (mRNAs) were quantified by Northern blot hybridization and expressed as a percentage of mRNA abundance in fed controls. In DSS mice, IL-1 beta mRNA was elevated in the fed group (954 +/- 155%; P < 0.001), but was suppressed in fasted animals (71.1 +/- 11%). IGF-I mRNA also was elevated in fed DSS mice (421 +/- 71%; P < 0.01). This increase was attenuated in fasted DSS mice (202 +/- 17%; P < 0.01 compared to fed DSS mice). Tumor necrosis factor-alpha mRNA was increased in fed DSS mice (162 +/- 15%; P < 0.01), but was not significantly lower in fasted animals. By in situ hybridization, IL-1 beta mRNA was localized to the lamina propria of colonic mucosa in fed DSS animals, but was not detectable in other groups. We conclude that fasting has a protective effect on the progression of acute DSS, induced colitis. This is associated with decreased expression of IL-1 beta and IGF-I mRNAs in the colon.
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PMID:Fasting prevents experimental murine colitis produced by dextran sulfate sodium and decreases interleukin-1 beta and insulin-like growth factor I messenger ribonucleic acid. 900 9

In inflammatory bowel disease, the colonic mucosa is infiltrated by inflammatory cells that secrete a variety of inflammatory mediators such as interleukin-1 beta (IL-1 beta). IL-1 beta caused a delayed increase in Cl- secretion and in prostaglandin E2 (PGE2) release in rabbit distal colon. Both of these effects were abolished with cycloheximide, implying a role for protein synthesis in mediating IL-1 beta's effect. With the use of Western blot assays, the protein was identified as the phospholipase A2 (PLA2)-activating protein (PLAP). IL-1 beta caused a concentration-dependent and a time-dependent increase in PLAP levels as well as in PLA2 activity, with the maximal increase observed at an IL-1 beta concentration between 10 and 30 ng/ml reached in 2-10 min. The PLAP mRNA levels were also regulated by IL-1 beta with a similar time course. PLAP is constitutively present in the epithelial cells and in the subepithelial layer of the distal colon. These findings suggest a direct effect of IL-1 beta on intestinal epithelial cells to cause an increase in PLAP levels and phospholipase A2 activity and subsequent increase in PGE2 levels.
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PMID:IL-1 beta induces synthesis of phospholipase A2-activating protein in rabbit distal colon. 922 68

Inflammatory bowel disease (IBD) is associated with increased activation of intestinal immune cells, whose overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) is implicated in mediating the sustained inflammatory response. Studies to date have largely reported qualitative differences in cytokine gene expression between IBD and controls. Our aim was to perform quantitative analysis of intestinal mucosal mRNA expression in colonic biopsies from pediatric IBD patients using a competitive polymerase chain reaction. IL-1 beta and TNF-alpha were expressed in all IBD and control biopsies. Compared to controls, IL-1 beta mRNA levels were increased in involved tissue from Crohn's disease (CD) patients, but not in histologically uninvolved CD or in ulcerative colitis (UC) mucosa. IL-1 beta expression in the latter groups were equivalent to those found in tissue from patients with eosinophilic colitis (EOC). Significantly higher levels of IL-1 beta mRNA were found in uninvolved mucosa from CD patients who presented with a relapse of disease activity, as compared to newly diagnosed cases with histological features of CD at an early stage. TNF-alpha mRNA transcripts were also significantly elevated in involved CD mucosa, but not in the other groups. TNF-alpha gene expression in CD-involved tissue decreased with disease duration. Follow-up of the patients revealed that high cytokine expression in uninvolved CD tissue correlated with an early clinical relapse. In conclusion, quantitative determination of proinflammatory cytokine gene expression reveals differences between the type, severity, and clinical course in patients with IBD.
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PMID:Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies. 924 63

Enhanced production of proinflammatory cytokines has been described in inflammatory bowel disease. The effect of interleukin (IL)-10, a cytokine with antiinflammatory activity, or anti-IL-10, on cytokine production by cultured colonic mucosa or blood mononuclear cells from patients with active inflammatory bowel disease was evaluated. Addition of IL-10 to the culture medium of colonic tissues or blood mononuclear cells resulted in inhibition of both IL-1 beta and tumor necrosis factor-alpha production and augmentation of IL-1 receptor antagonist production. Conversely, neutralization of endogenous IL-10 was found to augment both tumor necrosis factor-alpha and IL-1 beta production and inhibit IL-1 receptor antagonist production. In addition, the production of IL-10 by mononuclear cells was suppressed by prednisolone. In conclusion, IL-10 and related molecules may be useful in the treatment of inflammatory bowel disease.
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PMID:Therapeutic implications of interleukin-10 in inflammatory bowel disease. 965 53


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