Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine-based therapy for inflammatory bowel disease (IBD) has significantly advanced in the last year. This review highlights some of the exciting progress that has occurred. The efficacy of anti-tumor necrosis factor (TNF) monoclonal antibody therapy in Crohn's disease has promoted further research and the development of other anti-TNF therapies, such as thalidomide, phosphodiesterase type IV inhibitors, and new-generation anti-TNF monoclonal antibodies. Current research is also focused on more proximal events in the inflammatory cascade to modify T-cell regulation and to decrease the production and activity of proinflammatory proteins, cytokines, and nuclear regulatory factors. Concurrently, the emerging role of interleukin (IL)-11, IL-12, and IL-18 in the perpetuation of chronic inflammation continues to stimulate much interest. All of these new advancements reveal an exciting future for IBD therapy.
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PMID:Cytokine-based therapies in inflammatory bowel disease. 1702 62

IL-32 is the name given to the NK4 transcript first reported in IL-2 activated T lymphocytes and natural killer cells 13 years ago without known function. The novel cytokine has six isoforms. In an study to isolate a soluble form of the IL-32 receptor from human urine, IL-32alpha bound proteinase-3 with high affinity and was not affected by enzyme inhibition. IL-32alpha/IL-32gamma were expressed as recombinant molecules. The cytokine exhibits properties characteristic of proinflammatory cytokines and also induces the degradation of inhibitory kappaB and phosphorylation of mitogen activated protein p38. Monoclonal antibodies to IL-32 identify its presence in a variety of human tissues from diseases states. Epithelial cells from healthy subjects express low levels of the cytokine, but in disease conditions such as chronic obstructive pulmonary disease, Crohn's disease and psoriasis, the expression increases markedly. IL-32 is a major transcript in gene array studies in epithelial cells stimulated with IFNgamma in vitro. In rheumatoid arthritis, synovial tissues reveals increased content of IL-32, which correlates with severity of disease. A highly significant correlation has been observed between the number of synovial and macrophagic cells positive for IL-32 and the level of erythrocytes sedimentation, IL-1beta, tumour necrosis factor alpha, and IL-18. Thus, IL-32 exhibits many properties of proinflammatory cytokines and associations with disease severity.
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PMID:IL-32, a novel cytokine with a possible role in disease. 1703 76

CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn's disease (CD) and an increased frequency of CCR9(+) T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9(+) T cells in mucosal lymphoid tissues in CD. We show that CCR9(+) T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9(+) T cells isolated from CD SB lamina propria produced more IFN-gamma and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-gamma, but not IL-17, by CD lamina propria CCR9(+) T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVbeta analysis of CCR9(+) T cells revealed a diverse TCRVbeta repertoire among MLN CCR9(+) T cells in patients with SB CD. Our data indicate that CCR9(+) T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.
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PMID:Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease. 1731 80

Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
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PMID:Interleukin-18 and the pathogenesis of inflammatory diseases. 1733 92

Understanding cytokine immunobiology is central to the development of rational therapies for destructive inflammatory diseases such as rheumatoid arthritis (RA) and periodontitis. The classical interleukin-1 (IL-1) family cytokines, IL-1alpha and IL-1beta, as well as IL-18, play key roles in inflammation. Recently, other members of the IL-1 family have been identified. These include six cytokines whose genes are located downstream of the genes for IL-1alpha and IL-1beta on chromosome 2 (IL-1F5-10) and also IL-33, which is the ligand for ST2, a member of the IL-1R/Toll-like receptor (TLR) receptor superfamily. IL-1F6, IL-1F8 and Il-1F9 are agonists and, along with their receptor IL-1Rrp2, are highly expressed in epithelial cells suggesting a role in immune defence in the skin and the gastrointestinal (GI) tract including the mouth. Synovial fibroblasts and articular chondrocytes also express IL-1Rrp2 and respond to IL-1F8, indicating a possible role in RA. IL-33 is associated with endothelial cells in the inflamed tissues of patients with RA and Crohn's disease, where it is a nuclear factor which regulates transcription. IL-33 is also an extracellular cytokine: it induces the expression of T helper 2 (Th2) cytokines in vitro and in vivo as well as histopathological changes in the lungs and GI tract of mice. Therapeutic agents which modify IL-1 cytokines (e.g. recombinant IL-1Ra) have been used clinically and others are at various stages of development (e.g. anti-IL-18 antibodies). This review highlights the emerging data on these novel IL-1 cytokines and assesses their possible role in the pathogenesis and therapy of destructive inflammatory disorders such as RA and periodontitis.
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PMID:The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. 1759 Jan 66

Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
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PMID:Novel genetic markers in inflammatory bowel disease. 1794 29

Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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PMID:Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. 1884 65

Inflammatory bowel disease (IBD) includes two similar yet distinct conditions called ulcerative colitis (UC) and Crohn's disease (CD). These diseases affect the digestive system and cause the inflammation of intestinal tissue, form sores and bleed easily. Most children with IBD are diagnosed in late childhood and adolescence. However, both UC and CD have been reported as early as in infancy. Most information pertaining to the epidemiology of IBD is based upon adult studies. Symptoms include abdominal pain, cramping, fatigue and diarrhea. Genetic factors play a significant role in determining IBD susceptibility. Epidemiological data support a genetic contribution to the pathogenesis of IBD. Recently, numerous new genes have been identified as being involved in the genetic susceptibility to IBD: TNF-308A, CARD15 (NOD2), MIF-173, N-acetyltransferase 2 (NAT2), NKG2D (natural killer cell 2D), STAT6 (signal transducer and activator of transcription 6), CTLA-4 (cytotoxic T lymphocyte antigen-4), MICA-MICB (major histocompatibility complex A and B), HLA-DRB1, HLA class-II, IL-18, IL-4, MICA-A5, CD14, TLR4, Fas-670, p53 and NF-kappaB. The characterization of these novel genes has the potential to identify therapeutic agents and aid clinical assessment of phenotype and prognosis in patients with IBD (UC and CD).
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PMID:Epidemiology and gene markers of ulcerative colitis in the Chinese. 1923 40

TLR play important roles in inflammation and innate immune response to pathogens. TLR8 recognizes ssRNA and induces NF-kappaB via MyD88 signaling. TL1A is a member of the TNF superfamily that markedly enhances IFN-gamma production by IL-12/IL-18-stimulated peripheral and mucosal CD4(+) T cells. TL1A expression is increased in the mucosa of patients with inflammatory bowel disease and is considered a key mediator of Crohn's disease (CD). We have previously shown that TL1A is strongly induced by immune complexes (IC) but not TLR ligands in antigen-presenting cells. However, a potential interaction between these pro-inflammatory signaling pathways has not been investigated. IC-induced TL1A expression of monocytes was potently inhibited by a TLR8 or TLR7/8 ligand (R848) in a dose-dependent manner. Furthermore, when co-cultured with CD4(+) T cells, TLR8 ligands inhibited TL1A production, resulting in almost complete inhibition of IFN-gamma production by the CD4(+) T cells. Furthermore, we demonstrate that IFN-alpha is not required for this suppressive effect by TLR8 signaling. Our data demonstrate for the first time a direct interaction between TLR and TL1A signaling pathways. TLR8 activation may be an important, novel pathway for targeted treatment of Th1-mediated diseases, such as CD.
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PMID:TLR8-mediated activation of human monocytes inhibits TL1A expression. 1963 97

Intestinal alterations in IBD are triggered and maintained by an overexpression of proinflammatory cytokines. Additionally, increased immune activation has been found in the adjacent intestinal areas without displaying any apparent histological alterations, however, the regulatory environment is not well established. Biopsy specimens from patients with ulcerative colitis (UC) and Crohn's disease (CD), from both affected and unaffected areas, and also from a group of colonic biopsies from healthy controls, were included in our study. Cytokines and markers of mucosal damage were analyzed by real-time PCR, and some of the results confirmed by western-blot and ELISA. Levels of IFNgamma, TNFalpha, IL-6, IL-15, IL-18, and IL-23 were increased (above healthy controls) in both affected and unaffected areas from IBD. IL-1beta, IL-6, IL-12, and IL-27 were higher in affected areas compared to unaffected ones in UC but not CD. In general, a correlation was observed between mRNA levels of these cytokines and both iNOS and Granzyme B. SOCS-2 and SOCS-3 were also increased in the affected areas. In conclusion, the unaffected areas from IBD show increased levels of a restricted set of cytokines that may exert immune activating roles in these areas without being able to trigger tissue damage.
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PMID:High levels of proinflammatory cytokines, but not markers of tissue injury, in unaffected intestinal areas from patients with IBD. 1965 6


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