Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IBD is characterized by increased serum concentrations of different cytokines. IL-10 inhibits the production of proinflammatory cytokines such as IL-1, tumour necrosis factor-alpha (TNF-a), interferon-gamma (IFN-gamma) and IL-6 through inhibitory action on Th1 cells and macrophages, and it is thought to be a suppressor type cytokine. In the present study we determined serum concentrations of IL-10 in patients with ulcerative colitis (UC) and Crohn's disease (CD). We measured human IL-10 by our own newly established ELISA system using PharMingen antibodies. Serum antibodies were assessed in 44 patients with UC, 40 patients with CD, and in 30 healthy controls. Human IL-10 serum levels were significantly increased in patients with active UC (144 +/- 34 pg/ml (mean +/- s.e.m.), P < 0.001) and in active CD (132 +/- 32 pg/ml, P < 0.001) compared with healthy controls (44 +/- 9.5 pg/ml). Only patients with active CD and active UC presented with significantly increased IL-10 serum levels, while patients with inactive disease did not show any significant increase. There was no statistically significant difference between IL-10 serum levels in patients with CD or UC. Compared with clinical disease activity indices there was a significant correlation between IL-10 serum concentration and CDAI in patients with CD (r = 0.45, P < 0.01) and CAI in UC patients (r = 0.39, P < 0.05). Comparing IL-10 serum levels with serum concentrations of other proinflammatory cytokines there was a significant correlation to serum levels of sIL-2R (r = 0.417, P < 0.05) and IL-6 (r = 0.387, P < 0.05) in patients with CD. Serum cytokine levels in patients with UC did not show any significant correlation to IL-10 serum concentration. IL-10 is elevated in serum of patients with active CD and UC, suggesting that IL-10 acts as a naturally occurring damper in the acute inflammatory process of IBD.
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PMID:Circulating antiinflammatory cytokine IL-10 in patients with inflammatory bowel disease (IBD). 777 55

Hyporesponsiveness to a universe of bacterial and dietary antigens from the gut lumen is a hallmark of the intestinal immune system. Since hyperresponsiveness against these antigens might be associated with inflammation, we studied the immune response to the indigenous intestinal microflora in peripheral blood, inflamed and non-inflamed human intestine. Lamina propria monocuclear cells (LPMC) isolated from inflamed intestine but not peripheral blood mononuclear cells (PBMC) of IBD patients with active inflammatory disease strongly proliferated after co-culture with sonicates of bacteria from autologous intestine (BsA). Proliferation was inhibitable by anti-MHC class II MoAb, suggesting that it was driven by antigen. LPMC from adjacent non-inflamed intestinal areas of the same IBD patients and PBMC or LPMC isolated from non-inflamed intestine of controls and patients with IBD in remission, in contrast, did not proliferate. PBMC or LPMC which had been tolerant to bacteria from autologous intestine, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestine (BsH). This proliferation was associated with an expansion of CD8+ T cells, increased expression of activation markers on both CD4+ and CD8+ lymphocyte subsets, and production of IL-12, interferon-gamma (IFN-gamma), and IL-10 protein. These results show that tolerance selectively exists to intestinal flora from autologous but not heterologous intestine, and that tolerance is broken in intestinal inflammation. This may be an important mechanism for the perpetuation of chronic IBD.
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PMID:Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD) 853 55

Several theories have already been postulated in connection with the pathogenesis of inflammatory bowel diseases, yet none of them has been approved. Recently increasing attention has been payed to different cytokines, playing central role in the development of inflammatory processes. In the intestinal mucosa of patients suffering from inflammatory bowel diseases increasing amounts of interleukin-1 (IL-1), tumor necrosis factor (TNF) and platelet activating factor (PAF) could be measured. On the other hand, antiinflammatory cytokines seem to be ineffective, or being present in insufficient amount (IL-4 and IL-10 respectively). It is therefore probable, that altered ratios of cytokines, or pathologic regulation of their production lead to progression of inflammation in IBD. Influence of cytokine production may open new therapeutic approach, e.g. IL-10 enema proved to be effective in the treatment of some cases of steroid-resistant ulcerative colitis, while intravenous administration was useful in Crohn's disease. A brief, comprehensive review of our present knowledge about cytokines in IBD is given.
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PMID:[The role and significance of the most important known cytokines in inflammatory bowel diseases]. 963 23

Although the importance of genetic susceptibility to IBD has been established by epidemiological studies, the genes involved remain poorly characterized. Important candidate genes include those encoding the immunoregulatory cytokines IL-2 and IL-10. The aim of this study was to assess the contribution of the IL-2 and IL-10 genes to IBD susceptibility. One hundred and ninety-eight pairs of siblings with IBD were genotyped at dinucleotide repeat polymorphisms within the IL-2 and IL-10 genes, and data analysed by the affected sib-pair method of linkage analysis and the transmission disequilibrium test (TDT). A subset of 89 affected sibling pairs was genotyped at markers flanking the IL-2 gene as part of a genome-wide search. The IL-2 polymorphism showed no linkage to IBD overall, but modest evidence for linkage to the ulcerative colitis (UC) data set (P = 0.028). A microsatellite 4 cM distal to the IL-2 gene showed a similar distortion in the ulcerative colitis subgroup (P = 0.006). The TDT showed some distortion of allelic transmission for the IL-2 polymorphism in the UC group, but this did not reach statistical significance (P = 0.09). Results for the IL-10 polymorphism were not significant. Thus the gene encoding IL-2 may contribute to UC susceptibility, but the effect is modest and must await replication in other data sets. The IL-10 gene does not appear to contribute to the risk of developing UC or Crohn's disease.
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PMID:Contribution of the IL-2 and IL-10 genes to inflammatory bowel disease (IBD) susceptibility. 969 79

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

Inflammatory bowel disease therapy can be considered in several subcategories, and this review is designed to provide selective updates for some of the most important therapeutic entities currently marketed or soon to be available for the medical management of IBD. Although conventional corticosteroids have been a major component of acute inflammatory bowel disease management, steroids have many serious disadvantages; and toxicity is heightened with chronic steroid therapy. Newer corticosteroids, particularly budesonide, may be less toxic than older agents such as prednisone. Budesonide may be used as an enema in active distal ulcerative colitis (UC) or as delayed release tablets in Crohn's disease (CD). However, budesonide is not completely free from steroid side effects, and may share in some of the toxicity of older corticosteroids, particularly when high dose budesonide is administered. Topical and oral aminosalicylates are widely utilized for the treatment of mild to moderate active UC and mild active CD, and they also are efficacious for maintenance of IBD remission. Recent data continue to support the concept that higher doses and prolonged use of mesalamine-based drugs are therapeutically superior to lower doses and short term treatment. In addition, the combination of oral and rectal aminosalicylate formulations often succeeds in patients refractory to either used alone. The immunomodulatory drugs azathioprine and 6-mercaptopurine are particularly effective in treating both CD and UC, and methotrexate has also shown some promise in CD therapy. Immunosuppressive therapy for inflammatory bowel disease initially met with strong physician resistance. However, views have shifted in response to positive data on the utility of immunosuppressive agents in many cases of IBD. Although cyclosporine may be used as a 'rescue' medication in some severe IBD cases, it has been associated with severe toxic reactions. Possible candidates for cyclosporine treatment should be offered such therapy only in academic centers highly experienced with the nuances of this modality. Clinical trials of the newer entities IL-10, IL-11, tacrolimus, and anti-TNFalpha, have demonstrated variable efficacy in refractory IBD patients. Anti-TNFalpha has been very impressive, particularly in the presence of fistulizing Crohn's disease. Many physicians have utilized various antibiotics empirically as part of their 'general' management of IBD. Only metronidazole has been adequately studied in controlled CD trials, but other antibiotic studies are pending. Further exploration of antimicrobial treatment for IBD is clearly warranted. Many other investigational agents in disparate pharmaceutical categories have been employed in IBD therapy; and some of these also show varying degrees of promise, including the aloe vera derivative acemannan, several formulations of heparin, and both transdermal and intra-rectal nicotine. Despite the growing list of medications and formulations promoted for the treatment of IBD, no single drug or recognized combination has yet been confirmed as dependably clinically effective. Many additional investigations of IBD medical therapy are needed, including permutations of conventional medications, along with newer agents that may be more precisely targeted to specific aspects of IBD pathophysiology. All physicians who care for UC and CD patients enthusiastically await more optimal regimens for these challenging disorders.
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PMID:Medical therapy of inflammatory bowel disease for the 21st century. 1002 72

Looking back at successes and failures in newer approaches to treating IBD, it is tempting--although still difficult--to draw conclusions about pathogenesis. When a therapy proves effective, do clinicians truly know how it works? Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage. When a drug appears to be less effective than preclinical models suggest, can failures in effectiveness from delivery or dosing be differentiated? The disappointing results of clinical trials with IL-10--so at odds with the prediction of benefit from animal models--bring into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is judged. The variability of response even to the most narrowly targeted agents suggests that these diseases are far more heterogeneous in humans than in their murine counterparts. Clinicians are only just beginning to recognize subclinical markers of response, and it may soon be possible to predict response on the basis of genetic composition. For the moment, however, the field of pharmacogenetics is embryonic. Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level. Only through considered evaluation of clinical evidence may clinicians determine which therapies should remain novelties and which should become an accepted part of the armamentarium.
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PMID:Novel therapies for inflammatory bowel disease. 1037 71

Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are chronic inflammatory and frequently relapsing diseases of the gut that ultimately lead to destruction of the intestinal tissue. Recent evidence suggests that a pathologic activation of the mucosal immune system in response to antigens is a key factor in the pathogenesis of IBD. Furthermore, changes in cell migration and cytokine production appear to contribute to the perpetuation of IBD and the postoperative recurrence of Crohn's disease. Based on recent advances in our understanding of the pathogenesis of IBD, several new therapeutic strategies are currently being tested in clinical practice, including recombinant anti-inflammatory cytokines (IFN-alpha, IL-10, IL-11) and inhibitors of cell adhesion molecules (ICAM), proinflammatory cytokines (TNF, IL-12) and their receptors (TNF, IL-6R).
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PMID:[Immunopathogenesis of inflammatory bowel diseases]. 1066 99

Cytokines are the key mediators of inflammation in the IBD and are focus of renewed interest to plan therapeutic strategies against this disease. However, there are gaps in our knowledge at present and a lot of questions need clear answers. Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage. When a drug appears to be less effective than pre-clinical models suggest, can failures in effectiveness from delivery or dosing the differentiated? The disappointing results of clinical trials with IL-10 is at odds with the prediction of benefit from animal models. It even brings into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is assessed. Other exciting new methods to treat IBD could be use of monoclonal antibodies to effector T cell molecules (such as CD4 or CD44v7) removal of such cytokine secreting cells (apheresis), antibodies to proinflammatory cytokines (such as TNF-alpha, IFN-alpha, IFN-gamma, and IL-12) or administration of anti-inflammatory cytokines (such as IL-10, IL-11). Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level. There is also need to further refine our knowledge about genetic elements and environment initiators to comprehensively manage IBD.
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PMID:Cytokines and inflammatory bowel disease. 1069 14

Current therapy of inflammatory bowel disease, ie, ulcerative colitis and Crohn's disease, is neither sufficient nor disease-modifying. Long-term treatment with non-specific antiinflammatory drugs aminosalicylates, corticosteroids and immunosuppressants is often accompanied with undesirable and potentially serious side effects. Novel biologically-driven therapies are targeted to specific pathophysiological processes, offering the potential for better treatment outcomes. Among other antiinflammatory peptides and proteins, monoclonal antibodies directed against TNFalpha and adhesion molecule alpha4beta7 integrin, recombinant anti-inflammatory cytokines IL-10 and IL-11, as well as colony-stimulating factors and peptide growth factors, are in the most advanced stages of clinical development for IBD.
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PMID:Anti-inflammatory peptides and proteins in inflammatory bowel disease. 1189 Mar 53


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