Ulcerative Colitis: Zeitz M

Hoffmann JC, Zeitz M, Anonymous00195. · Medizinische Klinik I mit Schwerpunkt Gastroenterologie/Infektiologie/Rheumatologie Charité, Universitätsmedizin Berlin Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin. · Med Klin (Munich). · Pubmed #15654542 No free full text.

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Preiss JC, Blumenstein I, Zeuzem S, Zeitz M. · Medizinische Klinik I, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin. · Z Gastroenterol. · Pubmed #19533543 No free full text.

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Glauben R, Sonnenberg E, Zeitz M, Siegmund B. · Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Department I, Berlin, Germany. · Cancer Lett. · Pubmed #19101082 No free full text.

Abstract: Histone deacetylase (HDAC) inhibitors have been described in detail for their anti-proliferative potency. Recently, an anti-inflammatory property was characterized in vitro and in vivo. This dual efficacy of HDAC inhibitors is highly attractive, since chronic inflammations such as ulcerative colitis are associated with an increased risk of developing carcinomas. Additionally, in models of colitis and inflammation-induced tumorigenesis inflammation as well as tumor development was significantly inhibited by HDAC inhibitor treatment. The mechanisms involved reach beyond the simple regulation of histone acetylation and deacetylation. The currently known key target structures and mechanisms mediating this dual effect will be discussed in this review.

Preiss JC, Timmer A, Zeitz M, Hoffmann JC. · Medizinische Klinik I (Gastroenterologie/Infektiologie/Rheumatologie), Charité Campus Benjamin Franklin, Berlin. · Z Gastroenterol. · Pubmed #17924306 No free full text.

Abstract: The German Society for Digestive and Metabolic Diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, DGVS) has already published an impressive number of clinical practice guidelines, with more topics currently being under development. The guideline method within the DGVS as well as between medical professional societies varies greatly. In particular, the levels of evidence as well as the grades of recommendations are often applied very differently. Most guidelines in Germany use the grades of the US Agency for Health Care Policy and Research (AHCPR), which were first published in 1992. Some newer guidelines, e.g., the ulcerative colitis guideline of the DGVS or the guidelines of the German Diabetes Association, try to circumvent problems of this method. They adopted variations of the very simple AHCPR grades. Sometimes these new grading methods have serious shortcomings too. They may not be reproducible, ignore important parts of the consensus process, can only be applied to therapeutic interventions, or they do not adequately distinguish between the strength of a recommendation and the quality of evidence. Meanwhile, an enormous number of different and partially contradictory methodologies for the grading of guideline recommendations are being used. In the GRADE working group several renowned clinical epidemiologists came together to develop a uniform grading systematic that avoids the problems of earlier guideline methods. With GRADE first the quality of evidence is assessed in a systematic manner. The quality of each study plays an important role in this process. Hence randomised trials of poor quality can end up with a lower overall quality rating than well performed observational trials. The strength of recommendation is based on the balance between the expected benefit and harm of the intervention in the respective population for which the recommendations of the guideline are made. The quality of evidence is only one factor contributing to the strength of recommendation. The GRADE method can be more cumbersome in its application compared to older methods. Nevertheless, more and more organisations are adopting GRADE for their guidelines and recommendations. Possibly the DGVS guidelines could benefit from this new system too.

Siegmund B, Zeitz M. · Medizinische Klinik I, Charité Universitätsmedizin Berlin. · Praxis (Bern 1994). · Pubmed #16245638 No free full text.

Abstract: Ulcerative colitis was first described in 1859 from Samuel Wilks, a physician at Guy's hospital in London. The prevalence in the high incidence areas ranges from 80 to 120/100.000/year. Ulcerative colitis is a chronic relapsing or chronic active disease which starts at the rectum and presents with a continuous inflammation. Primarily young adults are affected (20 to 40 years of age) but the disease may present at all ages, from younger than 1 year of life to the 80s. Many series show a secondary peak in incidence in the elderly. In the present review we will focus on the basic principles of the therapy with regard to the variety of disease manifestations. The therapeutic algorithms will be described separately for the induction of remission and the maintenance of remission. The localization of inflammation and disease activity represent crucial factors which have to be considered. With regard to these factors, the therapeutic regimens range from simple local therapy with aminosalicylates to systemic immunosuppressive therapy, which will in extreme cases require the administration of ciclosporin. Since ulcerative colitis is associated with an increased risk in developing colon carcinoma, medical therapy as well as endoscopic surveillance are fundamental in the prevention of carcinoma. In the end an outlook to future therapeutic targets and strategies will be provided.

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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Wittig BM, Duchmann R, Stallmach A, Zeitz M. · Innere Medizin II, Universitätskliniken des Saarlandes, 66421 Homburg/Saar. · Internist (Berl). · Pubmed #11271620 No free full text.

This publication has no abstract.

Stange EF, Riemann J, von Herbay A, Lochs H, Fleig WE, Schölmerich J, Kruis W, Porschen R, Bruch HP, Zeitz M, Schreiber S, Moser G, Matthes H, Selbmann HK, Goebell H, Caspary WF. · Abteilung Innere Medizin 1 Robert-Bosch-Krankenhaus Auerbachstrasse 110 70376 Stuttgart. · Z Gastroenterol. · Pubmed #11215358 No free full text.

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Zeitz M. · Klinik für Innere Medizin II, Universitätskliniken des Saarlandes. · Med Klin (Munich). · Pubmed #10194948 No free full text.

Abstract: Corticosteroids and 5-amino salicylic acid (5-ASA) are established therapies in the induction of remission and in maintenance of remission in patients with ulcerative colitis. 5-ASA exists in different delivery systems, however, clinical studies directly comparing these preparations exist only in very limited numbers. When analyzing placebo-controlled or comparative studies it is clearly evident that 5-ASA is superior to placebo in both induction of remission and maintenance therapy. In maintenance therapy prodrug compounds (sulfasalazine, SASP) seem to be marginally better compared to 5-ASA slow release preparations. Direct comparison of the newer 5-ASA preparations is not possible because of limited data. Theoretical considerations based on the different principles of slow release are also questionable since the intraluminal pH or intestinal motility may be disturbed in IBD.

Bojarski C, Günther U, Rieger K, Heller F, Loddenkemper C, Grünbaum M, Uharek L, Zeitz M, Hoffmann JC. · Medical Department I Gastroenterology, Infectious Diseases, Rheumatology, Charité Campus Benjamin Franklin, Berlin, Germany. · Endoscopy. · Pubmed #19418398 No free full text.

Abstract: BACKGROUND AND STUDY AIMS: Conventional histology with hematoxylin and eosin (H&E) staining is the accepted standard for diagnosing acute intestinal graft-versus-host disease (GvHD). Confocal endomicroscopy (CEM) is a noninvasive method that allows in vivo histology to be performed during endoscopy. The aim of this study was to evaluate CEM for the diagnosis of acute intestinal GvHD. PATIENTS AND METHODS: This observational pilot study conducted between September 2006 and August 2008 included patients with acute diarrhea after stem cell transplantation, infectious diarrhea, or active ulcerative colitis. CEM (EC-3870CIFK, Pentax, Tokyo, Japan) was performed after intravenous injection of fluorescein 10% and topical application of acriflavine 0.05%. RESULTS: A total of 35 patients with acute diarrhea after stem cell transplantation were examined. In 16 patients, CEM and histology showed no evidence of GvHD. In 14/19 patients with histologically confirmed GvHD, the diagnosis could already be established by CEM during ongoing endoscopy. In GvHD grade IV, near complete destruction of the colonic crypts ("flat mucosa") was visible. Control patients with infectious colitis (N = 15) or ulcerative colitis (N = 15) displayed inflammatory changes but no evidence of GvHD. Altogether, sensitivity of CEM was 74% and specificity was 100 %. CONCLUSIONS: CEM improves rapid diagnosis of acute intestinal GvHD with high accuracy while performing endoscopy. Platelet transfusions and unnecessary biopsy acquisition can be avoided once acute intestinal GvHD has been diagnosed in vivo.

Niesner U, Albrecht I, Janke M, Doebis C, Loddenkemper C, Lexberg MH, Eulenburg K, Kreher S, Koeck J, Baumgrass R, Bonhagen K, Kamradt T, Enghard P, Humrich JY, Rutz S, Schulze-Topphoff U, Aktas O, Bartfeld S, Radbruch H, Hegazy AN, Löhning M, Baumgart DC, Duchmann R, Rudwaleit M, Häupl T, Gitelman I, Krenn V, Gruen J, Sieper J, Zeitz M, Wiedenmann B, Zipp F, Hamann A, Janitz M, Scheffold A, Burmester GR, Chang HD, Radbruch A. · German Rheumatism Research Center Berlin, 10117 Berlin, Germany. · J Exp Med. · Pubmed #18663125 links to  free full text

Abstract: The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-kappaB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Hoffmann U, Heilmann K, Hayford C, Stallmach A, Wahnschaffe U, Zeitz M, Günthert U, Wittig BM. · Medical Clinic 1, Department for Gastroenterology, Infectiology and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin D 12200, Germany. · Cell Death Differ. · Pubmed #17479111 links to  free full text

Abstract: Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an anti-CD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.

Visekruna A, Joeris T, Seidel D, Kroesen A, Loddenkemper C, Zeitz M, Kaufmann SH, Schmidt-Ullrich R, Steinhoff U. · Max Planck Institute of Infection Biology, Berlin, Germany. · J Clin Invest. · Pubmed #17124531 links to  free full text

Abstract: Enhanced NF-kappaB activity is involved in the pathology of both forms of inflammatory bowel disease (IBD), Crohn disease (CD) and ulcerative colitis (UC). Here we analyzed the mechanism of proteasome-mediated NF-kappaB activation in CD and UC. Our studies demonstrate that the subunit composition and the proteolytic function of proteasomes differ between UC and CD. High expression of the immunoproteasome subunits beta1i and beta2i is characteristic of the inflamed mucosa of CD. In line with this, we found enhanced processing of NF-kappaB precursor p105 and degradation of inhibitor of NF-kappaB, IkappaBalpha, by immunoproteasomes isolated from the mucosa of CD patients. In comparison with healthy controls and CD patients, UC patients exhibited an intermediate phenotype regarding the proteasome-mediated processing/degradation of NF-kappaB components. Finally, increased expression of the NF-kappaB family member c-Rel in the inflamed mucosa of CD patients suggests that p50/c-Rel is important for IFN-gamma-mediated induction of immunoproteasomes via IL-12-driven Th1 responses. These findings suggest that distinct proteasome subunits influence the intensity of NF-kappaB-mediated inflammation in IBD patients.

Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. · Department of Gastroenterology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. · Gut. · Pubmed #16822808 No free full text.

Abstract: BACKGROUND: Epithelial barrier function is impaired in Crohn's disease. AIM: To define the underlying cellular mechanisms with special attention to tight junctions. METHODS: Biopsy specimens from the sigmoid colon of patients with mild to moderately active or inactive Crohn's disease were studied in Ussing chambers, and barrier function was determined by impedance analysis and conductance scanning. Tight junction structure was analysed by freeze fracture electron microscopy, and tight junction proteins were investigated immunohistochemically by confocal laser scanning microscopy and quantified in immunoblots. Epithelial apoptosis was analysed in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and 4',6-diamidino-2-phenylindole staining. RESULTS: Patients with active Crohn's disease showed an impaired intestinal barrier function as indicated by a distinct reduction in epithelial resistance. As distribution of conductivity was even, focal epithelial lesions (eg, microerosions) did not contribute to barrier dysfunction. Instead, freeze fracture electron microscopy analysis showed reduced and discontinuous tight junction strands. Occludin and the sealing tight junction proteins claudin 5 and claudin 8 were downregulated and redistributed off the tight junction, whereas the pore-forming tight junctions protein claudin 2 was strongly upregulated, which constitute the molecular basis of tight junction changes. Other claudins were unchanged (claudins 1, 4 and 7) or not detectable in sigmoid colon (claudins 11, 12, 14, 15 and 16). Claudin 2 upregulation was less pronounced in active Crohn's disease compared with active ulcerative colitis and was inducible by tumour necrosis factor alpha. As a second source of impaired barrier function, epithelial apoptosis was distinctly increased in active Crohn's disease (mean (SD) 5.2 (0.5)% v 1.9 (0.2)% in control). By contrast, barrier function, tight junction proteins and apoptosis were unaffected in Crohn's disease in remission. CONCLUSION: Upregulation of pore-forming claudin 2 and downregulation and redistribution of sealing claudins 5 and 8 lead to altered tight junction structure and pronounced barrier dysfunction already in mild to moderately active Crohn's disease.

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.

Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. · Department of Gastroenterology, Charité, Campus Benjamin Franklin, Berlin, Germany. · Gastroenterology. · Pubmed #16083712 No free full text.

Abstract: BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines have not been shown to directly influence epithelial barrier function. METHODS: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT-29/B6 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. RESULTS: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13Ralpha1 and IL-4Ralpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. CONCLUSIONS: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity.

Siegmund B, Zeitz M. · Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik I, Hindenburgdamm 30, 12200 Berlin, Germany. · Gut. · Pubmed #15753520 links to  free full text

This publication has no abstract.

Hoffmann JC, Fischer I, Höhne W, Zeitz M, Selbmann HK. · Medizinische Klinik I mit Schwerpunkt Gastroenterologie/Infektiologie/Rheumatologie, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin. · Z Gastroenterol. · Pubmed #15455268 No free full text.

This publication has no abstract.

Scherübl H, Wittig BM, Hoffmann JC, Zeitz M. · Charité -- Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik I -- Gastroenterologie, Infektiologie und Rheumatologie. · Dtsch Med Wochenschr. · Pubmed #15368182 No free full text.

This publication has no abstract.

Amasheh S, Barmeyer C, Koch CS, Tavalali S, Mankertz J, Epple HJ, Gehring MM, Florian P, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. · Department of Clinical Physiology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. · Gastroenterology. · Pubmed #15188166 No free full text.

Abstract: BACKGROUND & AIMS: The main limiting factor for sodium absorption in distal colon is the amiloride-sensitive epithelial sodium channel (ENaC). This study aimed to characterize mechanisms involved in the dysregulation of ENaC expression in ulcerative colitis (UC). METHODS: Epithelial preparations from surgically removed inflamed and control sigmoid colons were used. Active electrogenic Na(+) transport (J(Na)) was determined after 8-hour aldosterone stimulation in Ussing-chambers (corrected for the altered epithelial/subepithelial resistance ratio). Subsequently, ENaC alpha-, beta-, and gamma-subunits were analyzed immunohistochemically and in Western and Northern blots (corrected for the inflammatory increase in subepithelial protein content). To study gene regulation, the promoters of beta- and gamma-ENaC were analyzed in reporter gene assays. RESULTS: In controls, aldosterone stimulated J(Na) and induced ENaC beta- and gamma-subunit expression, whereas this response was virtually abolished in UC. Preservation of surface epithelium in UC was indicated by unchanged ENaC alpha-subunit expression, which points also against a mere immaturity or epithelial cell loss. Inhibition of electrogenic sodium transport as well as beta- and gamma-ENaC mRNA expression could be mimicked in control colon by in vitro preexposure for 8 hours to tumor necrosis factor alpha and interferon gamma. Promoter analysis revealed that down-regulation of beta- and gamma-ENaC gene expression was primarily induced by tumor necrosis factor alpha. CONCLUSIONS: We conclude that, in UC, elevated proinflammatory cytokines selectively impair beta- and gamma-ENaC expression, which contributes to diarrhea by reducing colonic sodium absorption.

Barmeyer C, Horak I, Zeitz M, Fromm M, Schulzke JD. · Medical Clinic I - Gastroenterology, Infectious Diseases and Rheumatology, University Clinic Benjamin Franklin, Free University of Berlin, Berlin, Germany. · Pathobiology. · Pubmed #12571417 No free full text.

Abstract: Interleukin-2-deficient (IL-2(-/-)) mice develop colitis with striking clinical and morphological similarities to ulcerative colitis. Since transport and barrier properties are impaired in ulcerative colitis, we studied transport and barrier functions in IL-2(-/-) mice in order to gain insight for the first time into the general pathomechanisms of disturbed transport and barrier function of the intestine during inflammation. Alternating current impedance analysis was used to determine tissue conductance in the inflamed proximal colon of IL-2(-/-) mice and to discriminate between pure epithelial and subepithelial conductance. Surprisingly, epithelial conductance was not increased but diminished in IL-2(-/-) mice compared to controls (20.2 +/- 1.3 versus 28.8 +/- 2.8 mS/cm(2)). Concomitantly, conductance of the subepithelial tissue layers was decreased in IL-2(-/-) mice as a result of edema and infiltration with inflammatory cells. In the distal colon, electrogenic Na(+) transport (J(Na)) mediated by the epithelial Na(+) channel (ENaC) was measured 8 h after stimulation with 3.10(-9) M aldosterone in vitro as the drop in I(SC) (short circuit current) after addition of 10(-4) M amiloride. In controls, J(Na) was 6.9 +/- 0.9 micromol x h(-1) x cm(-2), whereas it was abolished in IL-2(-/-) mice. In conclusion, the inflamed colon of IL-2(-/-) mice exhibits a severe disturbance in Na(+) uptake via the ENaC in the absence of a barrier defect. Thus, reduced expression of active absorptive transport and not a barrier defect is responsible for the diarrhea in this model of intestinal inflammation. This makes this model suitable for studying the general pathomechanisms of the inflammatory downregulation of intestinal transport proteins.

Buergel N, Schulzke JD, Zeitz M. · Medizinische Klinik I-Gastroenterologie, Infektiologie und Rheumatologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin. · Chirurg. · Pubmed #12425157 No free full text.

Abstract: The etiology and pathogenesis of ulcerative colitis are still unclear. There is, however, a growing consensus that the disease is characterized by a complex interaction between genetic and environmental influences. Many studies in the last few years have suggested that appendectomy reduces the risk of development and improves the course of ulcerative colitis. The underlying mechanism of this effect is unknown. The appendix seems to play a more important role in the development and modulation of the mucosal immune system than believed so far.

Stallmach A, Marth T, Adrian N, Wittig BM, Ecker KW, Schilling M, Zeitz M. · Department of Internal Medicine II, Saarland University, 66421 Homburg, Germany. · Int J Colorectal Dis. · Pubmed #12172923 No free full text.

Abstract: BACKGROUND AND AIMS: Since interleukin-12 is pathogenetically involved in Crohn's disease (CD) but not in ulcerative colitis (UC), expression and mechanisms of induction of interleukin-12 receptor (IL-12R) subunits beta(1) and beta(2) were analyzed in lamina propria mononuclear cells (LPMNC) of patients with CD and UC. PATIENTS AND METHODS: LPMNC from patients with CD ( n=17), UC ( n=14), and controls ( n=19) were isolated by standard techniques. IL-12R beta(1) and IL-12R beta(2) transcripts were semiquantified by RT-PCR, and expression of IL-12R beta(2) chain was characterized by flow cytometry. LPMNC were activated by cross-linking with anti-CD3 antibodies and B7-1 costimulation. RESULTS: IL-12R beta(1) and IL-12R beta(2) transcript concentrations were higher in inflamed specimens than in noninflamed segments of patients with CD but not in UC. Increased percentage of mucosal CD4(+)/IL-12R beta(2)(+) cells was observed in active CD, but not UC. In vitro stimulation of LPMNC with anti-CD3 antibodies resulted in an increase in IL-12R beta(1) transcripts irrespective of B7-1 mediated costimulation (84% and 95%, respectively). However, increased expression of IL-12R beta(2) mRNA (110%) was detected only after B7-1 costimulation. CONCLUSION: Our data indicate that increased mucosal expression of IL-12R beta(2) on LPMNC in CD but not in UC may be the result of B7-1 costimulation. Modulation or inhibition of IL-12R beta(2) expression on LPMNC could provide a selective therapeutic approach in CD.

Pfister K, Wittig BM, Jüngling B, Ecker KW, Barth S, Huhn M, Sasse S, Engert A, Mueller-Molaian I, Diehl V, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg/Saar, Germany. · Int J Colorectal Dis. · Pubmed #12014425 No free full text.

Abstract: BACKGROUND AND AIMS: In chronic inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis an aberrant mucosal immune regulation is observed accompanied by upregulation of proinflammatory cytokines. Lamina propria T cells of inflamed mucosa have an activated phenotype characterized by increased expression of surface markers such as CD25. We therefore determined the anti-inflammatory effect of a recombinant immunotoxin consisting of an anti-CD25 single chain variable fragment (scFv) fused to a deletion mutant of Pseudomonas exotoxin A [RFT5(scFv)ETA'] on isolated lamina propria lymphocytes of patients with IBD and in the murine model of trinitrobenzene sulfonic acid (TNBS) induced colitis. PATIENTS AND/METHODS: Lamina propria lymphocytes of 25 patients with IBD and 19 control patients were stimulated in absence or presence of RFT5(scFv)ETA'. Interferon-gamma production was determined in the supernatant by ELISA and the induction of apoptosis by flow cytometry after propidium iodide staining. BALB/c mice received TNBS intrarectally and were treated with RFT5(scFv)ETA'. RESULTS: In vitro the administration of RFT5(scFv)ETA' significantly reduced interferon-gamma production and increased apoptosis in lamina propria lymphocytes isolated of inflamed mucosa. However, this contrainflammatory regulation did not result in gain of weight or increased life span in experimental colitis in vivo. CONCLUSION: In addition to the downregulation of the proinflammatory cytokine in vitro, RFT5(scFv)ETA' induced neither a direct nor a bystander effect in an in vivo model of colitis. Therefore our data do not support potential therapeutic implications of targeting CD25 by RFT5(scFv)ETA' in chronic IBD.

Pfister K, Wittig BM, Mueller-Molaian I, Remberger K, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Exp Mol Pathol. · Pubmed #11733944 No free full text.

Abstract: Splice variants of the glycoprotein CD44 are transiently expressed on lymphocytes during T cell activation. Increased expression of CD44v6 on peripheral blood lymphocytes (PBL) of patients with inflammatory bowel disease (IBD) was described recently. The aim of this study was therefore to characterize CD44v6 expression on CD4(+) lamina propria lymphocytes (LPL) of patients with active IBD in comparison to controls. CD44v6 expression on CD4(+) LPL (n = 19) of controls and patients with active IBD (Crohn's disease n = 14, ulcerative colitis n = 15) was analyzed by flow cytometry and compared to that on autologous PBL. Thereby, in vitro regulation of CD44v6 on LPL and PBL via CD3 and CD2 and the costimulatory signal B7-1 was examined. In addition, the role of protein kinase C (PKC) in CD44v6 expression was tested. CD44v6 expression was increased in CD4(+) LPL (median, 45%) compared to PBL (median, 38%). Surprisingly, in IBD CD44v6 was downregulated on CD4(+) lamina propria T cells, irrespective of their state of inflammation (median, 28%). CD44v6 expression on LPL was not upregulated upon CD3 activation alone but following costimulation with B7-1. However, CD2-mediated T cell activation sufficiently induced upregulation of CD44v6 on LPL and PBL. In our study, downregulation of CD44v6 on LPL of patients with IBD was not due to defective PKC activation. Taken together, these data indicate that decreased CD44v6 expression on LPL in IBD might be a feature of an inappropriate costimulatory signal in T cell activation.