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Inflamed Mucosa (inflamed + mucosa)
Selected AbstractsApoptosis resistance in ulcerative colitis: High expression of decoy receptors by lamina propria T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Raja Fayad Abstract Intestinal mucosa is constantly exposed to normal environmental antigens. A significant number of intestinal mucosal T cells are being deleted through apoptosis. In contrast, T cells from inflamed mucosa of ulcerative colitis patients did not undergo apoptosis. In this study, we determined whether the apoptosis of normal mucosal T cells was induced by antigen receptor stimulation and further determined pathways that mediated the apoptosis. Freshly isolated lamina propria T cells were stimulated with CD3 mAb and apoptosis was determined by Annexin,V staining. Normal mucosal T cells underwent apoptosis upon CD3 mAb stimulation whereas the T cells from inflamed mucosa did not. The apoptosis in normal T cells was blocked by TRAIL-R1:Fc and an inhibiting CD95 antibody. Interestingly, decoy receptor (DcR)1, DcR2, and DcR3 that compete with death receptor (DR)4/5 and CD95 were highly expressed by the T cells from inflamed mucosa, but much lower by T cells from normal mucosa. Our data suggest that normal mucosal T cells are constantly deleted in response to environmental antigens mediated through DR4/5 and CD95 pathways and mucosal T cells from ulcerative colitis resist to undergoing apoptosis due to highly expression of DcR1, DcR2, and DcR3. [source] Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis,INFLAMMATORY BOWEL DISEASES, Issue 7 2010Sunil Yeruva PhD Abstract Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na+/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-,), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ,80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients. (Inflamm Bowel Dis 2010) [source] Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naïve ulcerative colitis during active and quiescent diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2009Reikei Matsuda MD Abstract Background: Cytokines have validated roles in the immunopathogenesis of inflammatory bowel disease (IBD). This study was to investigate the expressions of tumor necrosis factor (TNF)-,, interleukin (IL)-6, IL-8, and IL-10 mRNAs in the colonic mucosa of patients with ulcerative colitis (UC) during active and quiescent UC. Methods: At colonoscopy, biopsies were taken from inflamed and non-inflamed mucosa of patients with steroid-naive UC (n = 15), non-IBD inflammatory colitis controls (ICC, n = 6), and non-colitis controls (NCC, n = 14). The presence of extensive mononuclear cells and neutrophils infiltrate in the lamina propria, cryptitis, and epithelial damage defined an inflammatory lesion in the mucosa. Quantitative cytokine mRNA expressions in biopsies were measured by real-time polymerase chain reaction (PCR). Results: Of 15 UC patients, 3 remitted with 5-aminosalicylate and 11 received granulocytapheresis; of these, 10 remitted. At baseline, IL-6, IL-8, TNF-,, and IL-10 mRNAs were high in inflamed mucosa compared with NCC (P < 0.01). In active UC, IL-6, IL-8 and IL-10 mRNAs were high compared with non-inflamed mucosa (P = 0.03, P = 0.03, P < 0.05, respectively). Both TNF-, mRNA (P = 0.03) and IL-6 mRNA (P = 0.04) were higher in UC compared with ICC. Even in non-inflamed mucosa, IL-8 and TNF-, mRNA expressions were high compared with NCC. Both IL-6 and IL-8 mRNAs decreased to normal levels after granulocytapheresis. Conclusions: During active UC, all 4 cytokine mRNA levels were high; only IL-6 and IL-8 mRNAs decreased to normal levels during remission. IL-8 mRNA was high even at sites of endoscopically quiescent UC during active disease. Steroid naïve patients respond well to granulocytapheresis. (Inflamm Bowel Dis 2008) [source] Mucosal NOD2 expression and NF-,B activation in pediatric Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2008Laura Stronati PhD Abstract Background: Recent advances in the pathogenesis of Crohn's disease (CD) have suggested that an aberrant innate immune response initiates the cascade of events leading to T-cell activation and to disease development. NOD2 protein, which is mainly expressed by innate immunity cells, appears to play a key role against bacteria by triggering a host defense response through the activation of the transcriptor factor NF-,B and a consequent proinflammatory cytokine production. The present study was aimed at investigating the expression and activity of NOD2, NF-,B, and of 2 proinflammatory cytokines, TNF, and IL-1,, in mucosal biopsies of CD affected children compared to healthy controls. Methods: In all, 22 children with active CD and 10 matched controls were entered in the study. mRNA and protein expressions were detected using reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot; NF-,B binding activity was assessed by electromobility gel shift assay (EMSA). Results: NOD2 and IL-1, mRNAs were upregulated in CD children. Protein levels of NOD2, TNF,, and nuclear NF-,B, as well as the binding activity of NF-,B to a consensus DNA sequence, were significantly increased in inflamed mucosa of patients as compared to controls. Moreover, NF-,B activity was strongly upregulated in patients also when bound to the NOD2 promoter site. No difference was seen between patients and controls when NF-,B binding activity was determined in the uninflamed tissue. Conclusions: This study suggests that altered mechanisms regulating NOD2 induction, NF-,B activation and cytokine production may contribute to dysregulate the innate immune response underlying pediatric CD. (Inflamm Bowel Dis 2007) [source] Local and systemic interleukin-18 and interleukin-18-binding protein in children with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 1 2008Steven T. Leach Abstract Background: Interleukin-18 (IL-18) is increased in the inflamed mucosa of patients with Crohn's disease (CD). The balance between this pleiotropic proinflammatory cytokine and its natural inhibitor, IL-18-binding protein (IL-18BP), may contribute to the pathogenesis of inflammatory bowel disease (IBD). Methods: Serum and mucosal biopsies were collected from children with IBD, from children with celiac disease, and from controls. Biopsies were maintained in culture for 24 hours, and supernatant was collected. Serum and supernatant IL-18 and IL-18BPa concentrations were measured by immunoassay. Disease activity score (PCDAI) and standard serum inflammatory markers (albumin, platelets, ESR, and CRP) were recorded. Results: Serum IL-18 was greater in children with CD (537 pg/mL) than in controls (335 pg/mL; P < 0.05) but not in children with ulcerative colitis (UC) or IBD type unclassified (IBDU). Mucosal IL-18 was greater in children with CD and UC/IBDU than in controls (P < 0.01). Serum IL-18BPa was increased in children with CD compared with that in controls (3.9 versus 2.6 ng/mL; P < 0.05), but was not elevated in children with UC/IBDU. Furthermore, calculated free-serum IL-18 was elevated in CD, but not UC/IBDU, compared with that in controls (P = 0.001). Total and free-serum IL-18 were elevated in severe CD relative to in mild/moderate disease. Conclusions: IL-18, produced in the colons of children with IBD, may contribute to local inflammatory changes. Systemic IL-18 level may be a useful indicator of gut inflammation. Furthermore, free IL-18 is greatly elevated in children with CD, suggesting that compensatory increases in IL-18BPa are insufficient. Further exploration of the role of this cytokine in the pathogenesis of IBD is now required. (Inflamm Bowel Dis 2007) [source] Differential expression of CCR5 and CRTH2 on infiltrated cells in colonic mucosa of patients with ulcerative colitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2003KOJI MATSUZAKI Abstract Background and Aim:, The pathogenesis of ulcerative colitis (UC) is unclear, but abnormal infiltration of T lymphocytes in the colonic mucosa has been implicated in the mucosal tissue damage. The abnormal cytokine production because of a T helper (h)1/Th2 imbalance may play an important role in continuing inflammation in the colonic mucosa. In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients. Methods:, Tissue samples were obtained by colonic biopsies from patients with UC or colonic polyps, with informed consent. Immunohistochemical analysis was performed on periodate, lysine-paraformaldehyde-fixed serial cryostat sections using the labeled streptavidin biotin method. Monoclonal antibodies against CD4, CCR5 or CRTH2 were used as primary antibodies. The number of cells expressing CD4, CCR5 or CRTH2 per unit area was calculated by using an image analyzer. Results:, In the patients with UC, the numbers of CD4- and CCR5-positive cells were significantly increased in inflamed mucosa, and appeared to be correlated with the disease activity. The infiltration of CRTH2-positive cells was predominantly observed in the mildly inflamed or the margin of inflamed mucosa of UC patients. Conclusion:, There is a possibility that Th1 responses significantly occur in colonic mucosa with severe inflammation, while Th2 responses mainly occur with mild inflammation in UC patients. The Th1/Th2 imbalance in colonic mucosa may be related to the disease progression of UC. [source] Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic miceJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2003TAKAHIRO ISHIKURA Abstract Background and Aim:, The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. Methods:, Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. Results:, The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. Conclusions:, These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice. [source] Altered expression of MUTYH and an increase in 8-hydroxydeoxyguanosine are early events in ulcerative colitis-associated carcinogenesis,THE JOURNAL OF PATHOLOGY, Issue 1 2009Masaki Gushima Abstract 8-Hydroxy-guanine (8-OH-G) mismatches readily with adenine residues, leading to a G : C to T : A transversion mutation. The human mutY homologue (MUTYH) excises adenine misincorporated opposite 8-OH-G during replication and suppresses mutations caused by reactive oxygen species. We defined the expression of 8-hydroxydeoxyguanosine (8-OHdG) and MUTYH in ulcerative colitis (UC)-associated neoplasia by immunohistochemistry and compared this with expression in UC patients without neoplasia and patients unaffected by UC. We also performed mutation analyses for MUTYH and K- ras. 8-OHdG was expressed more intensely in the mucosa of UC-associated neoplasia and UC without neoplasm than in the mucosa unaffected by UC. Immunohistochemistry with two different types of MUTYH antibody showed that UC-associated neoplasia and UC without neoplasia exhibited strong cytoplasmic expression and attenuated nuclear expression of MUTYH when compared with patients unaffected by UC. No pathological MUTYH mutations were detected in any of the UC-associated neoplasia cases. However, K- ras mutation was detected in two cases, one of which showed G : C to T : A transversion mutation and attenuated nuclear staining of MUTYH. In conclusion, inflamed mucosa of UC is exposed to oxidative damage. An increase in cytoplasmic MUTYH, rather than its mutation, may contribute to the promotion of carcinogenesis in UC. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitisARTHRITIS & RHEUMATISM, Issue 4 2009Francesco Ciccia Objective Subclinical gut inflammation is common in spondylarthritis, but the immunologic abnormalities underlying this process are undefined. Perturbation of the interleukin-23 (IL-23)/Th17 axis has emerged as a fundamental trigger of chronic inflammation. This study was undertaken to investigate the expression and tissue distribution of IL-23/Th17,related molecules in Crohn's disease (CD) and in subclinical gut inflammation in ankylosing spondylitis (AS). Methods Quantitative gene expression analysis of Th1/Th2 and IL-23/Th17 responses was performed in intestinal biopsy samples obtained from 12 patients with CD, 15 patients with AS, and 13 controls. IL-23 tissue distribution and identification of IL-23,producing cells were evaluated by immunohistochemistry. Results We demonstrated a strong and significant up-regulation of IL-23p19 transcripts in the terminal ileum in patients with AS and patients with CD. IL-23 was abundantly produced by infiltrating monocyte-like cells in inflamed mucosa from AS and CD patients. Notably, we also identified Paneth cells as a major source of IL-23 in patients with AS, patients with CD, and normal controls. Unlike CD, in AS patients, IL-23 was not associated with up-regulation of IL-17 and the IL-17,inducing cytokines IL-6 and IL-1,. Finally, while the Th1-related cytokines interferon-,, IL-12p35, and IL-27p28 were overexpressed only in CD patients, IL-4, IL-5, and STAT-6 were also significantly increased in AS patients. Conclusion Our findings indicate that overexpression of IL-23, but not IL-17, is a pivotal feature of subclinical gut inflammation in AS. Identification of resident Paneth cells as a pivotal source of IL-23 in physiologic and pathologic conditions strongly suggests that IL-23 is a master regulator of gut mucosal immunity, providing a pathophysiologic significance to the reported association between IL-23 receptor polymorphisms and intestinal inflammation. [source] Treatment of Distal Colitis with Local Anaesthetic AgentsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2002Stellan Björck The original observation was an adrenergic hyperinnervation of the inflamed mucosa (hyperinnervation hypothesis). In order to silence local nervous reflexes, the mucosa was treated topically with 2% lidocaine gel. The clinical results are promising and no side effects have been observed. The relapse rate is relatively high and related to the duration of treatment. In studies of experimental colitis a potential antagonism between harmful adrenergic nerves (vasoconstrictor substances and proinflammatory cytokines) and mucosa-protective visceral afferents (antiinflammatory cytokines) in the pathogenesis of colitis is intriguing. Other studies have emphasized the importance of neutrophils for causing damage to the colon epithelium (neutrophil hypothesis) and local anaesthetics have potent effects on several steps of the inflammatory response in addition to the nervous blockade. [source] | ||||||||||