Ulcerative Colitis: Rogler G

Vavricka SR, Rogler G. · Klinik für Gastroenterologie und Hepatologie, Department für Innere Medizin, Universitätsspital Zürich. · Praxis (Bern 1994). · Pubmed #19224489 No free full text.

Abstract: The therapy of ulcerative colitis is dependent on disease activity and on disease location. Different therapy concepts are applied in ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis as well as in chronic active disease and maintenance of remission. This overview presents important concepts in the treatment of ulcerative colitis.

Herfarth H, Rogler G. · Dept. of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Endoscopy. · Pubmed #15657857 No free full text.

Abstract: This review summarizes important publications that have appeared during the last year dealing with imaging techniques and endoscopy, as well as the management of low-grade dysplasia and stenosis in inflammatory bowel disease. Magnetic resonance enteroclysis and capsule endoscopy are currently emerging as new imaging techniques for the small bowel in Crohn's disease. While magnetic resonance enteroclysis is, at least in Europe, increasingly being used as a reference method, the value of capsule endoscopy for the management of inflammatory bowel disease is still being evaluated. Chromoendoscopy is being studied in patients with long-lasting ulcerative colitis and may be a promising and sensitive technique for the diagnosis of dysplasia. However, there are conflicting data regarding the appropriate management when low-grade dysplasia is diagnosed in patients with ulcerative colitis. Endoscopic dilation can often be successfully carried out in cases of intestinal stenosis. The results of long-term follow-up studies indicate that several dilation procedures are often necessary and that a relatively high percentage of patients still have to undergo surgery.

Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ, Dignass A, Fischer I, Fleig W, Fölsch UR, Herrlinger K, Höhne W, Jantschek G, Kaltz B, Keller KM, Knebel U, Kroesen AJ, Kruis W, Matthes H, Moser G, Mundt S, Pox C, Reinshagen M, Reissmann A, Riemann J, Rogler G, Schmiegel W, Schölmerich J, Schreiber S, Schwandner O, Selbmann HK, Stange EF, Utzig M, Wittekind C. · Medizinische Klinik I mit Schwerpunkt Gastroenterologie/Infektiologie/Rheumatologie, Charité, Universitätsmedizin Berlin. · Z Gastroenterol. · Pubmed #15455267 No free full text.

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Rogler G, Schölmerich J. · Klinik und Poliklinik für Innere Medizin I, Universität Regensburg, Regensburg. · Med Klin (Munich). · Pubmed #15024484 No free full text.

Abstract: Extraintestinal manifestations of Crohn's disease and ulcerative colitis are found in > 50% of all patients. These extraintestinal manifestations sometimes impair the overall life quality much more than the bowel-related symptoms. Extraintestinal manifestations need to be distinguished from secondary diseases or complications of inflammatory bowel diseases, as they require a different and specific therapy. Complications of the intestinal disease, such as vitamin deficiency or osteoporosis, can be treated specifically by substitution of vitamin D, calcium, or other vitamins. However, extraintestinal manifestations of Crohn's disease and ulcerative colitis, such as primary sclerosing cholangitis, arthritis or granulomatous inflammation of the skin, lung, or liver, are much more difficult to treat sufficiently. Almost every organ can be a localization of extraintestinal symptoms of inflammatory bowel diseases. It is important to acquire knowledge on these extraintestinal manifestations of Crohn's disease and ulcerative colitis to start the respective treatment early. Perhaps even more important, these extraintestinal symptoms can be the primary manifestation of Crohn's disease and ulcerative colitis. Therefore, they have to be recognized as extraintestinal manifestations to adequately treat the intestinal disease.

Fölsch UR, Hoffmann J, Höhne W, Janke KH, Klump B, Rogler G, Schreiber S. · Klinik für Allgemeine Innere Medizin, I. Medizinische Klinik, Universitätsklinikum Kiel, Schittenhelmstrasse 12, 24105 Kiel. · Internist (Berl). · Pubmed #12524923 No free full text.

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Andus T, Klebl F, Rogler G, Bregenzer N, Schölmerich J, Straub RH. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Aliment Pharmacol Ther. · Pubmed #12562454 links to  free full text

Abstract: BACKGROUND: Dehydroepiandrosterone is a steroid hormone used as an 'over-the-counter' drug in the USA. Treatment with dehydroepiandrosterone was effective in randomized controlled trials in patients with systemic lupus erythematosus. Dehydroepiandrosterone sulphate concentrations are decreased in patients with inflammatory bowel disease. Dehydroepiandrosterone inhibits nuclear factor-kappaB and the secretion of interleukin-6 and interleukin-12 via the peroxisome proliferator-activated receptor alpha. AIM: A phase II pilot trial was started to evaluate the effect of dehydroepiandrosterone in active inflammatory bowel disease. METHODS: Twenty patients with chronic active inflammatory bowel disease [seven Crohn's disease (Crohn's disease activity index, 242 +/- 51; mean +/- s.d.); 13 ulcerative colitis (clinical activity index, 7.8 +/- 2.1)] took 200 mg dehydroepiandrosterone per day orally for 56 days. RESULTS: Six of the seven patients with Crohn's disease and eight of the 13 patients with ulcerative colitis responded to treatment, with a decrease in the Crohn's disease activity index of > 70 points and a decrease in the clinical activity index of > 4 points, respectively. Six Crohn's disease patients and six ulcerative colitis patients went into remission (Crohn's disease activity index < 150; clinical activity index <or= 4). No patient withdrew from the study because of side-effects. CONCLUSIONS: In a pilot study, dehydroepiandrosterone was effective and safe in patients with refractory Crohn's disease or ulcerative colitis. Adjustment of the dehydroepiandrosterone dosage may further improve the treatment success.

Rogler G, Gelbmann CM, Vogl D, Brunner M, Schölmerich J, Falk W, Andus T, Brand K. · Dept. of Internal Medicine I, University of Regensburg, Germany. · Scand J Gastroenterol. · Pubmed #11336164 No free full text.

Abstract: BACKGROUND: Fibroblasts and myofibroblasts are known to secrete a wide spectrum of cytokines, but the individual spectrum is tissue-specific. We investigated the effect of cell activation on cytokine secretion of isolated human colonic fibroblasts/myofibroblasts from control patients and patients with mucosal inflammation. METHODS: Primary cultures of human colonic submucosal fibroblasts/myofibroblasts were incubated with IL-1alpha (100 U/ml), IL-Ibeta (10 ng/ml), IL-10 (10 ng/ml), TNF (10 ng/ml), PMA (10 ng/ml), LPS (50 ng/ml), IL-4 (10 ng/ml), or a combination of IL-1 and TNF. Secreted cytokines were determined by ELISA. NF-kappaB activation was demonstrated by electrophoretic mobility-shift assays (EMSA). RESULTS: Incubation of colonic fibroblasts/myofibroblasts with IL-1, LPS, TNF and PMA induced secretion of IL-6, IL-8, M-CSF and GM-CSF. IL-8 and IL-6 secretion could be stimulated by IL-1alpha, IL-1beta, TNF, PMA and LPS within 6 h of incubation. IL-6 secretion was stimulated from 0.5 +/- 0.01 pg/h x microg fibroblast protein to 18.5 +/- 2.6 pg/h x microg fibroblast protein with IL-1beta (P < 0.01). IL-8 secretion was stimulated from 1.0 +/- 0.1 pg/h x microg fibroblast protein to 41.1 +/- 3.6 pg/h x microg (P < 0.005). IL-4 and IL-10 did not change cytokine secretion significantly. No significant differences between cultures from normal and inflamed mucosa were observed. TNF and IL-1 induced NF-kappaB activation. ALLN, a proteasome and NF-kappaB activation inhibitor, reduced TNF-mediated IL-8, GM-CSF and M-CSF induction significantly, whereas induction of IL-6 secretion remained unchanged. CONCLUSION: Human colonic myofibroblasts can secrete large amounts of IL-6, IL-8, M-CSF and GM-CSF upon stimulation. The induction of IL-8, M-CSF and GM-CSF, but not of IL-6 secretion, is mediated mainly by NF-kappaB activation. The cytokine profile and the total amounts of cytokines released suggest that colonic myofibroblasts can play a role in leukocyte recruitment and during mucosal inflammation. They therefore have to be regarded as an important part of the mucosal immune system.

Gnewuch C, Liebisch G, Langmann T, Dieplinger B, Mueller T, Haltmayer M, Dieplinger H, Zahn A, Stremmel W, Rogler G, Schmitz G. · Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, Regensburg, Germany. · World J Gastroenterol. · Pubmed #19575493 links to  free full text

Abstract: AIM: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations. METHODS: Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS: Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohn's disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION: Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations.

Ott C, Obermeier F, Thieler S, Kemptner D, Bauer A, Schölmerich J, Rogler G, Timmer A. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #18794607 No free full text.

Abstract: OBJECTIVE: Although important advances in understanding the aetiology and pathogenesis of inflammatory bowel disease (IBD) have been made, many questions remain unanswered. As the most recent data available on the incidence of IBD in Germany were collected about 15 years ago, we set up a new population-based cohort to determine current incidence data for a defined region in Germany and to establish a basic cohort for prospective follow-up. METHODS: All patients living in the region of Oberpfalz newly diagnosed with IBD between 1 January 2004 and 31 December 2006 were included in this study by setting up a network of reporting clinicians and general practitioners in hospitals as well as in private practices. Demographic and clinical characteristics such as age at first diagnosis, localization of the disease, extraintestinal manifestations or family history on IBD were documented. Age-adjusted incidence rates are presented with 95% Poisson confidence intervals (CIs), based on the European standard population. RESULTS: In total, 286 newly diagnosed patients with IBD were reported in this region, 168 patients suffering from Crohn's disease (CD), 105 patients with ulcerative colitis. Age-standardized incidence rates were 11.0/10(5) (95% CI: 9.1-11.6) for IBD, 6.6/10(5) (95% CI: 5.6-7.7) for CD and 3.9/10(5) (95% CI: 3.2-4.7) for ulcerative colitis. Peak incidences were found in the age interval of 16-24 years for both diseases, predominantly for CD. Age at first diagnosis was lower, extraintestinal manifestations and a positive family history on IBD were more common in patients with CD. CONCLUSION: The incidence rate in IBD seems to be stable in Germany as compared with previously reported data, as is the remarkable predominance of CD. Prospective follow-up studies will be based on this incidence cohort.

Hafner S, Timmer A, Herfarth H, Rogler G, Schölmerich J, Schäffler A, Ehrenstein B, Jilg W, Ott C, Strauch UG, Obermeier F. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #18467916 No free full text.

Abstract: BACKGROUND: Environmental factors are likely to be involved in the pathogenesis of inflammatory bowel disease (IBD), as the incidence of both Crohn's disease (CD) and ulcerative colitis (UC) increased with improved living standards in Europe after World War II. On the basis of earlier reports suggesting that hygienic standards may also play a role in the pathogenesis of IBD, we investigated the influence of hepatitis A seroprevalence as an indicator for poorer hygienic conditions and worm infestations in IBD. METHODS: Hepatitis A seroprevalence was examined in patients with UC and CD. Patients with minor endocrinological disorders served as controls. All patients were questioned about immunizations, parasitic infections (worms), contact with animals, living on a farm, and ever traveling abroad. Patients were excluded for active hepatitis A immunization or recent passive immunization. Results are presented as Mantel-Haenszel odds ratios with 95% confidence interval, adjusted for age group. RESULTS: The sample included 307 patients (73 CD, 48 UC, and 186 controls). Hepatitis A seroprevalence was strongly associated with age older than 50 years. Age adjusted Mantel-Haenszel odds ratios were 0.25 (0.09-0.71) for UC and 0.75 (0.38-1.46) for CD versus controls. For parasitic infections, the odds ratios were 1.15 (0.52-2.53) for UC and 0.34 (0.13-0.89) for CD. CONCLUSION: We were able to demonstrate a negative association of hepatitis A infection with UC only. In contrast, a novel finding was a strong protective effect of worm infestations for the occurrence of CD, but not UC.

Hausmann M, Paul G, Kellermeier S, Frey I, Schölmerich J, Falk W, Menzel K, Fried M, Herfarth H, Rogler G. · Department of Internal Medicine I, University of Regensburg, Germany. · Clin Exp Immunol. · Pubmed #18460015 links to  free full text

Abstract: Haem oxygenase-1 (HO-1) up-regulation was suggested to reduce mucosal tissue damage in inflammatory bowel disease (IBD) and an up-regulation of HO-1 expression in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated. A HO-1 gene promoter microsatellite (GT)(n) dinucleotide repeat polymorphism was associated with regulation of HO-1 in response to inflammatory stimuli. We therefore hypothesized that IBD patients might segregate into phenotypes with high or low HO-1 inducibility. Ethylenediamine tetraacetic acid blood samples were obtained from 179 CD patients, 110 UC patients and 56 control patients without inflammation. Genomic DNA was purified and the 5'-flanking region of the HO-1 gene containing the (GT)(n) dinucleotide repeat was amplified. Polymerase chain reaction (PCR) products were purified and the length of the PCR fragments was analysed. The number of (GT)(n) repeats in the population studied ranged from 13 to 42. The distribution of the allele frequencies was comparable in patients and controls for both the short and the long alleles. The frequencies of short-, middle- and long-sized alleles were not changed among the groups studied. No correlation was found between IBD and microsatellite instability detected in five individals. Our data indicate that (GT)(n) dinucleotide repeats of the HO-1 promotor region have no significance for the pathophysiology and disease course of IBD.

Lippert E, Gunckel M, Brenmoehl J, Bataille F, Falk W, Scholmerich J, Obermeier F, Rogler G. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Clin Exp Immunol. · Pubmed #18336593 links to  free full text

Abstract: Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.

Hausmann M, Paul G, Menzel K, Brunner-Ploss R, Falk W, Schölmerich J, Herfarth H, Rogler G. · Department of Internal Medicine, University Hospital of Zurich, Switzerland. · Z Gastroenterol. · Pubmed #18322880 No free full text.

Abstract: BACKGROUND: 5- Aminosalicylic acid (5-ASA) is metabolised in colonic mucosa by N-acetyltransferase 1 (NAT1). Common genetic polymorphisms in this enzyme result in rapid or slow acetylation. 5-ASA treatment causes side effects in up to 10 % of patients with ulcerative colitis (UC). We therefore determined genetic variations of NAT1 in patients with UC and looked for a possible association with the clinical response to 5-ASA. METHODS: DNA was obtained from 78 patients with UC. 77 % of the patients were in remission during 5-ASA treatment, whereas 23 % suffered from active disease. NAT1 genotyping was performed for 23 known alleles using RFLP and sequence analysis. Clinical response to 5-ASA was determined by medical record review and associated with NAT1 genotypes. RESULTS: Utilising PCR we amplified a 570-bp coding region of the human NAT1 gene in addition to 240 bp in the 3'-untranslated region (UTR). 4 NAT1 alleles previously known as NAT1*3, *4, *10 and *11 were recovered. 31 % of the patients were heterozygous and 4 % homozygous for the NAT1*10 allele. 6 % were heterozygous for the NAT1*3 allele. 6 % were heterozygous for the NAT1*11 allele. No association was found between NAT1 genotype and clinical response as well as side effects to 5-ASA in patients with UC. CONCLUSIONS: NAT1 genotypes do not predict response or side effects to mesalamine in patients with UC. Variations caused by non-genomic effects may be associated with the clinical response to 5-ASA.

Altmann R, Hausmann M, Spöttl T, Gruber M, Bull AW, Menzel K, Vogl D, Herfarth H, Schölmerich J, Falk W, Rogler G. · Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany. · Biochem Pharmacol. · Pubmed #17604003 No free full text.

Abstract: BACKGROUND: The ligand activated nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) induces transcriptional repression of pro-inflammatory factors. Activation of PPARgamma is followed by amelioration of colitis in animal models of inflammatory bowel disease (IBD). A reduced expression of PPARgamma was found in epithelial cells of patients with ulcerative colitis. The eicosanoids 13-HODE and 15-HETE are products of 12/15-lipoxygenase (LOX) and endogenous ligands for PPARgamma. Dehydrogenation of 13-HODE by 13-HODE dehydrogenase results in formation of the 13-Oxo-ODE. Highest activity of 13-HODE dehydrogenase is found in colonic epithelial cells (CECs). We therefore investigated whether 13-Oxo-ODE is a new endogenous ligand of PPARgamma in CECs. METHODS: LOX activity and 13-HODE dehydrogenase in CECs were investigated after stimulation with arachidonic or linoleic acid. LOX metabolites were identified by RP-18 reversed-phase HPLC. Binding of (14)C-labelled 13-Oxo-ODE was demonstrated using a His-tagged PPARgamma. RESULTS: Stimulation of HT-29 and primary CECs homogenates with and without Ca-ionophor was followed by the formation of high amounts of the linoleic acid metabolite 13-Oxo-ODE (155 and 85 ng/ml). The decrease of IL-8 secretion from IEC was more pronounced after pre-incubation with 13-Oxo-ODE compared to the PPARgamma agonist troglitazone and higher as with the known PPARgamma ligands 13-HODE and 15-HETE. Binding assays with (14)C-labelled 13-Oxo-ODE clearly demonstrated a direct interaction. CONCLUSION: High amounts of 13-Oxo-ODE can be induced in CECs by stimulation of linoleic acid metabolism. 13-Oxo-ODE binds to PPARgamma and has anti-inflammatory effects. 13-HODE dehydrogenase might be a therapeutic target in IBD.

Kaltz B, Bokemeyer B, Hoffmann J, Porschen R, Rogler G, Schmiegel W. · Die Institutsangaben sind am Ende des Beitrags gelistet. · Z Gastroenterol. · Pubmed #17427117 No free full text.

Abstract: It has been assumed that cancer surveillance colonoscopy in patients with ulcerative colitis is not conducted according to the guidelines in Germany. An inquiry of the self-help organisation German Crohn's Disease/Ulcerative Colitis Association (DCCV) among organisation members belonging to colorectal cancer risk groups confirmed that the number of biopsies taken during colonoscopy is less than that proposed by the guidelines. Only with 9.2 % of the risk group did a guideline-conformal colonoscopy take place. In more than 50 % of the cases less than 10 biopsies were taken.

Shkoda A, Werner T, Daniel H, Gunckel M, Rogler G, Haller D. · Else-Kroener-Fresenius Center for Experimental Nutritional Medicine, Molecular Nutrition, Technical University of Munich, Freising-Weihenstephan, Germany. · J Proteome Res. · Pubmed #17330946 No free full text.

Abstract: The loss of intestinal epithelial cell (IEC) function is a critical component in the initiation and perpetuation of chronic intestinal inflammation in the genetically susceptible host. We applied proteome analysis (PA) to characterize changes in the protein expression profile of primary IEC from patients with Crohn's disease (CD) and ulcerative colitis (UC). Surgical specimens from 18 patients with active CD (N = 6), UC (N = 6), and colonic cancer (N = 6) were used to purify primary IEC from ileal and colonic tissues. Changes in protein expression were identified using 2D-gel electrophoreses (2D SDS-PAGE) and peptide mass fingerprinting via MALDI-TOF mass spectrometry (MS) as well as Western blot analysis. PA of primary IEC from inflamed ileal tissue of CD patients and colonic tissue of UC patients identified 21 protein spots with at least 2-fold changes in steady-state expression levels compared to the noninflamed tissue of control patients. Statistical significance was achieved for 9 proteins including the Rho-GDP dissociation inhibitor alpha that was up-regulated in CD and UC patients. Additionally, 40 proteins with significantly altered expression levels were identified in IEC from inflamed compared to noninflamed tissue regions of single UC (N = 2) patients. The most significant change was detected for programmed cell death protein 8 (7.4-fold increase) and annexin 2A (7.7-fold increase). PA in primary IEC from IBD patients revealed significant expression changes of proteins that are associated with signal transduction, stress response as well as energy metabolism. The induction of Rho GDI alpha expression may be associated with the destruction of IEC homeostasis under condition of chronic intestinal inflammation.

Spoettl T, Hausmann M, Klebl F, Dirmeier A, Klump B, Hoffmann J, Herfarth H, Timmer A, Rogler G. · Department of Internal Medicine I, University of Regensburg, Germany. · Inflamm Bowel Dis. · Pubmed #17260368 links to  free full text

Abstract: BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine and an important mediator in the pathophysiology of inflammatory bowel disease (IBD). The effects of TNFalpha are mediated by 2 specific receptors, a 55-kDa protein (TNF-RI) and a 75-kDa receptor (TNF-RII), which are usually bound to the cell surface. Soluble TNF receptors I and II (sTNF-RI + II) are released by proteolytic cleavage of the extracellular domains of these receptors. Soluble TNF-Rs act as TNF antagonists and can inhibit TNFalpha-mediated proinflammatory effects. METHODS: Levels of sTNF-RI + II were measured using commercially available enzyme-linked immunosorbent assays (ELISAs). Serum levels of sTNF-RI + II of 76 healthy volunteers were compared to serum levels of 373 clinically well-characterized patients with Crohn's disease (CD) and 118 patients with ulcerative colitis (UC) with different disease activity from the German IBD competence network serum bank. CD patient subgroups were defined according to the Vienna Classification. RESULTS: The serum levels of sTNF-RI were significantly increased in all groups (active, chronic active, and remission) of CD and UC patients compared to healthy controls. sTNF-RII levels were significantly higher in active CD patients compared to UC patients with no overlap of the 95% confidence interval. Significantly higher values of sTNF-RII compared to controls were also observed in CD patients and UC patients in remission. There was no statistically significant difference in sTNF-RI or sTNF-RII levels when patient subgroups were analyzed according to disease behavior or disease localization. CONCLUSION: sTNF-RI is upregulated in the serum of IBD patients compared to healthy controls and could be used as a marker for disease activity. sTNF-RII levels are significantly more elevated in serum of active CD patients as compared to UC and could be used as an additional parameter to discriminate both diseases.

Shkoda A, Ruiz PA, Daniel H, Kim SC, Rogler G, Sartor RB, Haller D. · Else-Kroener-Fresenius Center for Experimental Nutritional Medicine, Technical University of Munich, 85350 Freising-Weihenstephan, Germany. · Gastroenterology. · Pubmed #17241871 No free full text.

Abstract: BACKGROUND & AIMS: The initiation of endoplasmic reticulum (ER)-mediated stress responses in intestinal epithelial cells (IEC) may contribute to the pathogenesis of chronic intestinal inflammation. The aim of the study was to use functional epithelial cell proteomics to characterize anti-inflammatory mechanisms of interleukin 10 (IL-10). METHODS: Primary IEC were isolated from Enterococcus faecalis-monoassociated IL-10-deficient (IL-10-/-) and wild-type mice to perform 2D-gel sodium-dodecyl-sulfate polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. In addition, IEC from 6 patients with active Crohn's disease, ulcerative colitis, and sigmoid diverticulitis as well as noninflamed controls were purified. Molecular protective mechanisms of IL-10 were characterized in tumor necrosis factor (TNF)-stimulated IL-10 receptor (IL-10R) reconstituted epithelial cells. RESULTS: Primary IEC from IL-10-/- mice as well as inflammatory bowel disease patients revealed increased expression levels of the glucose-regulated ER stress protein (grp)-78 under conditions of chronic inflammation. Consistent with the observation that TNF induced ER stress responses through grp-78 redistribution from the ER lumen to the cytoplasmic IkappaB kinase complex, grp-78 knockdown completely abolished TNF-induced nuclear factor-kappaB RelA phosphorylation in epithelial cell cultures. Interestingly, IL-10 inhibited grp-78 protein and messenger RNA expression in IL-10R reconstituted IEC. Chromatin immunoprecipitation analysis and immunofluorescence microscopy revealed that IL-10-mediated p38 signaling inhibited TNF-induced recruitment of the ER-derived activating transcription factor (ATF)-6 to the grp-78 promoter likely through the blockade of ATF-6 nuclear translocation. CONCLUSIONS: Primary IEC from inflamed IL-10-/- mice and inflammatory bowel disease patients revealed activated ER stress responses in the intestinal epithelium. IL-10 inhibits inflammation-induced ER stress response mechanisms by modulating ATF-6 nuclear recruitment to the grp-78 gene promoter.

Spoettl T, Paetzel C, Herfarth H, Bencherif M, Schoelmerich J, Greinwald R, Gatto GJ, Rogler G. · Department of Internal Medicine I, University of Regensburg, 93042, Regensburg, Germany. · Int J Colorectal Dis. · Pubmed #16715250 No free full text.

Abstract: BACKGROUND: Nicotine is of therapeutic value in ulcerative colitis, but its administration is connected with adverse events. Nicotine derivatives are currently being tested to maintain the therapeutic effects and minimize adverse events. TC-2403-12 is a (E)-metanicotine hemigalactarate. The aim of this study was to determine the effectiveness of TC-2403-12 in the inhibition of TNF- and lipopolysaccharide (LPS)-induced cell activation. METHODS: Colonic epithelial cells (CEC), monocytes (MM6), granulocytes, and the intestinal epithelial cell line HT-29 were stimulated with TNF and LPS and treated with TC-2403-12. IL-8 secretion in the cell supernatants and NF-kappaB activation were determined by ELISA. Apoptosis was quantified by flow cytometry. RESULTS: In MM6 cells, IL-8 secretion was significantly decreased to 30% of control after TC-2403-12 treatment, with best results after pretreatment for 24 h. This decrease in cell activation was not due to apoptosis and was not mediated by inhibition of NF-kappaB activation. IL-8 production in neutrophils and primary CEC also tended to be decreased after TC-2403-12 treatment. TC-2403-12 had no influence on IL-8 secretion of HT-29 cells. CONCLUSION: TC-2403-12 effectively inhibited TNF- and LPS-induced IL-8 production in different cell types. No toxic effects occurred at the concentrations used. Preincubation of cells with TC-2403-12 showed the best effects.

Sina C, Schreiber S, Hoffmann JC, Rogler G, Schölmerich J, Zeitz M, Fölsch UR. · Klinik für Allgemeine Innere Medizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel. · Med Klin (Munich). · Pubmed #16501914 No free full text.

Abstract: The competence network chronic inflammatory bowel disease (KN-CED) is one of 17 networks of competence initiated by the German Federal Ministry of Education and Research (BMBF). These networks are concerned with disease patterns which are characterized by their high frequency, high mortality rate or which present a large expense factor. The project-executing organization is the German Center for Air and Space Travel (DLR e. V.). The central structure of organization is the Telematic Platform for medical Networks (TMF e. V.).Aim of the KN-CED is to investigate, in their complexity, the incurable chronic diseases ulcerative colitis and Crohn's disease, particularly with regard to the causes of disease, the establishment of new therapy standards as well as patient care.To achieve this goal, the competence network is integrated into both national and international research associations and is also backed by the national self-help group DCCV and the pharmaceutical industry.Principal items of the competence network are the core facilities and their main focus on molecular genetics, animal and cell models and serum markers. Having stored the data of more than 4,000 patients so far, the central database of the competence network is one of the largest databases worldwide with regard to inflammatory bowel disease (IBD).The successful cooperation within the network is reflected in numerous publications. Thus, two of the three known genes of Crohn's disease were identified. Also with the participation of the competence network national guidelines for the diagnosis and therapy of IBD were generated.Furthermore, the competence network operates study centers where significant therapeutic developments in the field of biotechnological drugs are taking place.The analysis of existing structures of care as well as the development of standards of organization for patients with IBD top the research within the competence network and emphasize the claim to find comprehensive answers to the questions connected with IBD.

McCole DF, Rogler G, Varki N, Barrett KE. · Department of Medicine, School of Medicine, University of California, San Diego, 92103, USA. · Gastroenterology. · Pubmed #16083715 No free full text.

Abstract: BACKGROUND & AIMS: Epidermal growth factor receptor (EGFR) activation, which plays an important role in regulating intestinal ion transport, can alleviate clinical symptoms such as diarrhea in patients with ulcerative colitis and promote mucosal restitution in animal models of colitis. Here, we investigate whether EGFR can regulate colonic ion transport in the setting of colitis. METHODS: Distal colon from control mice and mice with colitis was retained for immunohistochemistry or mounted in Ussing chambers. Ion transport responses across the tissues to the calcium agonist carbachol and the adenosine 3',5'-cyclic monophosphate agonist forskolin were measured with or without epidermal growth factor (EGF) pretreatment. RESULTS: EGF pretreatment of normal colonic mucosa inhibited ion transport responses to carbachol and forskolin but potentiated the reduced ion transport responses seen in dextran sulfate sodium (DSS)-treated and mdr1a knockout mouse colon. Ion substitution studies and the sodium transport inhibitor amiloride showed that sodium movement primarily accounted for the potentiating effect of EGF in DSS-treated tissues, despite decreased sodium channel expression. EGF potentiation of transport responses in DSS-treated colon was completely blocked by the cytoskeletal disruptor cytochalasin D and the phosphatidylinositol 3-kinase inhibitor wortmannin, whereas the novel and conventional protein kinase C isoform inhibitor Gö6850 and the extracellular signal-regulated kinase inhibitor PD98059 partially reduced EGF effects. EGFR epithelial distribution and transforming growth factor alpha expression were also altered in DSS-treated tissues. CONCLUSIONS: Chronic inflammation uncovers a potentiating effect of EGFR activation on epithelial electrogenic sodium absorption that would be expected to ameliorate diarrheal symptoms associated with colitis.

Furth EE, Li J, Purev E, Solomon AC, Rogler G, Mick R, Putt M, Zhang T, Somasundaram R, Swoboda R, Herlyn D. · Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, 19104, USA. · Cancer Immunol Immunother. · Pubmed #16034560 No free full text.

Abstract: PURPOSE: The gastrointestinal carcinoma-associated antigen epithelial cell adhesion molecule (EpCAM) has been a target for passive and active immunotherapy of gastrointestinal carcinoma patients. The antigen is expressed by both tumor and normal tissues. The immunogenicity of EpCAM in colorectal cancer patients has been described previously. The purpose of this study was to evaluate humoral and cellular immune responses of healthy individuals and ulcerative colitis patients to EpCAM and to relate immune responses to colonic tissue expression of EpCAM. METHODS: An inhibition radioimmunoassay was used to detect anti-EpCAM serum antibodies. Anti-EpCAM antibodies of a healthy donor were expressed by phages and sequenced. (3)H-thymidine incorporation assay was used for detection of lymphoproliferative responses to stimulation with EpCAM. EpCAM tissue expression was determined by immunohistochemistry. RESULTS: We detected anti-EpCAM serum antibodies in 4 of 10, and EpCAM-specific lymphoproliferation responses in 1 of 10 healthy volunteers. The majority of anti-EpCAM antibodies derived from a healthy donor were germline-encoded. In contrast, none of the 23 patients with ulcerative colitis showed serum antibodies to EpCAM (P=0.005). Antigen expression was greatly reduced and altered in ulcerative colitis patients, whereas colon from healthy individuals and uninvolved colon of colorectal cancer patients expressed high levels of EpCAM. CONCLUSION: The results of these studies suggest an association between EpCAM antibody production and colonic EpCAM expression in healthy individuals and patients with ulcerative colitis. Decreased and altered colonic EpCAM expression in ulcerative colitis patients may be related to the disease induction, based on the previously demonstrated adhesion function of this molecule. Healthy individuals with anti-EpCAM immune responses and high risk for developing colorectal carcinoma are prime candidates for prophylactic immunization against EpCAM.

Schreiter K, Hausmann M, Spoettl T, Strauch UG, Bataille F, Schoelmerich J, Herfarth H, Falk W, Rogler G. · Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany. · Gut. · Pubmed #15951537 links to  free full text

Abstract: BACKGROUND: The glycoprotein (gp) 96 links the adaptive with the innate immune system. It is a chaperone with a binding domain for peptides generated by proteasomal degradation. During cellular stress, peptide loaded gp96 can be released and presented to T cells by antigen presenting cells (APCs). METHODS: mRNAs from in vitro differentiated macrophages (iv mac) and normal intestinal macrophages (IMACs) were compared by subtractive hybridisation and Affymetrix GeneChip analysis. Differentiation induced expression of gp96 was investigated in the multicellular spheroid (MCS) model. In vivo gp96 protein expression was detected by double labelling immunohistochemistry of human colon and in the CD4+ CD62L+ T cell transfer mouse model. RESULTS: Five of 76 clones obtained by subtractive hybridisation revealed >99% sequence homology to gp96. Affymetrix GeneChip analysis confirmed induction of gp96 in IMACs. Gp96 mRNA was detected in IMACs from normal and intestinal bowel disease mucosa. Induction of gp96 protein was observed after seven days in the MCS model of IMAC differentiation. Immunohistochemistry confirmed the presence of gp96 protein in IMACs in normal mucosa as well as in mucosa from patients with ulcerative colitis and diverticulitis. In mucosa from Crohn's disease (CD) patients, gp96 protein was not detectable. In the CD4+ CD62L+ T cell transfer mouse model, gp96 was verifiable in non-activated IMACs. CONCLUSION: Gp96 is induced during differentiation of normal IMACs but is not detected in IMACs in CD mucosa. As gp96 has been described as having a role in tolerance induction, this may be relevant for loss of tolerance against luminal bacteria found in CD patients.

Paul G, Bataille F, Obermeier F, Bock J, Klebl F, Strauch U, Lochbaum D, Rümmele P, Farkas S, Schölmerich J, Fleck M, Rogler G, Herfarth H. · Department of Internal Medicine I, University of Regensburg, Germany. · Clin Exp Immunol. · Pubmed #15932518 links to  free full text

Abstract: Haem-oxygenase-1 (HO-1) has been shown to exert anti-inflammatory, anti-apoptotic and anti-proliferative effects. We investigated HO-1 expression in patients with inflammatory bowel disease (IBD) and could demonstrate a scattered expression of HO-1 in the intestinal epithelium of severely inflamed colonic mucosa of patients with IBD compared to control specimens such as diverticulitis, suggesting dysregulated expression in IBD. To further analyse potential mechanisms of HO-1 induction in the intestine we employed an in vitro epithelial cell apoptosis model and an experimental colitis model. In vitro induction of HO-1 by the HO-1 inducer cobalt protoporphyrin (CoPP) resulted in a dose-dependent down-regulation of caspase-3 activation in HT-29 cells, indicating an anti-apoptotic function of HO-1 in the intestine. In vivo, preventive HO-1 induction by CoPP in acute dextran sodium sulphate (DSS)-induced colitis led to a significant down-regulation of colonic inflammation (P < 0.01) with a concomitant reduction in interferon (IFN)-gamma - but unaffected interleukin (IL)-10-secretion by isolated mesenteric lymph nodes (P < 0.01). Additionally, TUNEL staining of colonic sections demonstrated fewer apoptotic epithelial cells in the colon of CoPP treated animals. No beneficial effects were observed if HO-1 was induced by CoPP after the onset of acute colitis or in chronic DSS-induced colitis. In conclusion, the data suggest a protective role of HO-1 if it is induced before the onset of inflammation. However, as shown by the lack of effects in established acute or in chronic colitis, the induction of HO-1 may not be a promising approach for the treatment of IBD.

Plikat K, Rogler G, Schölmerich J. · Klinik & Poliklinik fur Innere Medizin I, Universitat Regensburg, Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #15879729 No free full text.

Abstract: BACKGROUND: Anemia often occurs in patients with inflammatory bowel diseases. However, hemolytic anemia is a rare complication and is associated with Coombs-positive autoimmune disorders. There are several reports of autoimmune hemolytic anemia in patients with ulcerative colitis, whereas there are only four reports of this complication in patients with Crohn's disease. We report a case of a severe course Coombs-positive hemolytic anemia in a patient with Crohn's disease, which was refractory to medical treatment but resolved after subtotal colectomy. CASE REPORT: A 29-year-old patient was submitted to our clinic several times because of a severe course of inflammatory bowel disease and additionally a Coombs-positive autoimmune hemolytic anemia. Histology indicated severe Crohn's disease, but neither medical treatment with steroids, nor with methotrexate, cyclosporine or tumor necrosis factor-alpha antibody had been successful in resolving the intestinal inflammation and the hemolytic anemia. As colonoscopy revealed a pancolitis and dysplastic changes, even in the less inflamed areas of the colonic mucosa, subtotal colectomy was indicated. Half a year later we observed clinical and immunological signs of complete remission (no gastrointestinal symptoms, negative Coombs test). CONCLUSION: Autoimmune hemolytic anemia is a rare complication of inflammatory bowel disease and has been almost exclusively described in ulcerative colitis. The etiology is not yet completely understood. Presumably, the colon displays a role in the production of anti-erythrocyte antibodies. The therapy of choice in Crohn's associated hemolytic anemia is thought to be medical treatment with corticoid steroids. Some authors additionally prefer immunmodulators. However, in the case presented, colectomy (without splenectomy) was necessary to resolve refractory hemolysis and the severe course of Crohn's disease.