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Markus F Neurath

Publications and source records attributed to Markus F Neurath.

At least 55 records · Page 3Linked to original sources
PubMed2004

Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7.

CD4(+)CD25(+) regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-beta is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4(+)CD25(-) peripheral murine T cells. Similarly, TGF-beta induced Foxp3 in human CD4(+)CD25(-) T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-beta and limits TGF-beta signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4(+)CD25(-) T cells highly susceptible to the morphogenic and regulatory effects of TGF-beta signaling via Smad3/4. In summary, we demonstrate that TGF-beta induces a regulatory phenotype in CD4(+)CD25(-) T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-beta signaling due to the absence of Smad7.

Animals↗
PubMed2004

Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

Animals↗
PubMed2004

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Animals↗
PubMed2004

IL-6 trans-signaling: the heat is on.

The molecular consequence of the fever response has been illuminated by a recent study showing that a temperature shift to 40 degrees C resulted in increased leukocyte adhesion to tissue sections, which was mediated by L-selectin activation in lymphocytes. This L-selectin activation during heat responses was dependent on IL-6 trans-signaling via the soluble IL-6R.

Animals↗
PubMed2004

An innate cell-mediated, murine ulcerative colitis-like syndrome in the absence of nuclear factor of activated T cells.

BACKGROUND & AIMS: Nuclear factor of activated T cells transcription factors plays a central role in immunity by regulating the expression of multiple cytokines and other regulatory molecules, many of which have been heavily implicated in the pathogenesis of inflammatory bowel disease. However, few studies have directly investigated the nuclear factor of activated T cells proteins in inflammatory bowel disease. We describe here a specific role for nuclear factor of activated T cells c2 in the pathogenesis of murine inflammatory bowel disease. METHODS: Mice deficient for nuclear factor of activated T cells c2, recombinase activating gene-2, or both and transgenic or nontransgenic for an anti-ovalbumin T-cell receptor or an anti-hen egg lysozyme B-cell receptor were studied. Adoptive transfers were performed of T or B cells or both from nuclear factor of activated T cells c2-deficient mice into nuclear factor of activated T cells c2-deficient recombinase activating gene-deficient animals, in the presence or absence of antibodies that neutralize interleukin-10 activity. RESULTS: Nuclear factor of activated T cells c2-deficient, recombinase activating gene-deficient animals spontaneously developed a severe inflammatory bowel syndrome that resembled ulcerative colitis but was composed entirely of nonlymphocytes. The disease was suppressed by the adoptive transfer of polyclonal B-cell populations, even on neutralization of interleukin-10, but not by the presence of monoclonal T or B cells. CONCLUSIONS: Nuclear factor of activated T cells plays a critical role in the regulation of bowel inflammation by nonlymphoid immune cells, and B cells suppress bowel inflammation by innate immune cells. Such findings indicate a novel, interleukin-10-independent role for nuclear factor of activated T cells in the regulation of innate immunity and in intestinal immune tolerance.

Animals↗
PubMed2004

Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.

BACKGROUND & AIMS: A confocal laser endoscopy system has recently been developed that may allow subsurface imaging of living cells in colonic tissue in vivo. The aim of the present study was to assess its potential for prediction of histology during screening colonoscopy for colorectal cancer. METHODS: Twenty-seven patients underwent colonoscopy with the confocal endoscope using acriflavine hydrochloride or fluorescein sodium with blue laser illumination. Furthermore, 42 patients underwent colonoscopy with this system using fluorescein sodium. Standardized locations and circumscript lesions were examined by confocal imaging before taking biopsy specimens. Confocal images were graded according to cellular and vascular changes and correlated with conventional histology in a prospective and blinded fashion. RESULTS: Acriflavine hydrochloride and fluorescein sodium both yielded high-quality images. Whereas acriflavine hydrochloride strongly labeled the superficial epithelial cells, fluorescein sodium offered deeper imaging into the lamina propria. Fluorescein sodium was thus used for the prospective component of the study in which 13,020 confocal images from 390 different locations were compared with histologic data from 1038 biopsy specimens. Subsurface analysis during confocal laser endoscopy allowed detailed analysis of cellular structures. The presence of neoplastic changes could be predicted with high accuracy (sensitivity, 97.4%; specificity, 99.4%; accuracy, 99.2%). CONCLUSIONS: Confocal laser endoscopy is a novel diagnostic tool to analyze living cells during colonoscopy, thereby enabling virtual histology of neoplastic changes with high accuracy. These newly discovered diagnostic possibilities may be of crucial importance in clinical practice and lead to an optimized rapid diagnosis of neoplastic changes during ongoing colonoscopy.

Acriflavine↗
PubMed2004

Chromoendoscopy and magnifying endoscopy in patients with gastroesophageal reflux disease. Useful or negligible?

Gastroesophageal reflux disease (GERD) is common in the Western world. Upper endoscopy is needed to characterize the disease. Barrett's esophagus as a complication of GERD is an established precancerous condition which can lead to adenocarcinoma in the distal esophagus. This review summarizes recent advances in the endoscopic characterization of Barrett's esophagus using magnification endoscopy and chromoendoscopy. Methylene blue, indigo carmine and acetic acid are commonly used dyes to facilitate diagnosis of Barrett's esophagus. Methylene blue is absorbed in the specialized columnar epithelium, which is pathognomonic for Barrett's esophagus. Indigo carmine and acetic acid are used as contrast stains to highlight the surface architecture. Currently, different dyes are used in conjunction with magnifying endoscopes to characterize specific surface patterns of Barrett's epithelium. However, the current proposed classifications are too complex relative to their clinical value. Nevertheless, simplification of these systems will occur over time with increased use of magnifying chromoendoscopy. The value of magnifying chromoendoscopy for clinical practice is not determined yet and currently under investigation. However, these techniques have significant potential to improve diagnostic accuracy in patients with Barrett's esophagus.

Acetic Acid↗
PubMed2004

Differential TNF-signaling in chronic inflammatory disorders.

TNF-alpha is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF-strategies have proven to be clinically effective. Two TNF-specific cell surface receptors TNF-R1 and TNF-R2 have been identified and the function of these receptors and the downstream intracellular signal transduction pathways have been extensively studied in vitro. For a long time TNF-R1 was considered to be the predominant mediator of TNF-signaling, whereas TNF-R2 was ascribed only auxilliary function. However, there is increasing clinical and experimental evidence for an important independent role of p80 signaling in chronic inflammatory conditions. It is conceivable that the multiple TNF-mediated chronic inflammatory disorders differ in terms of the ligand form (soluble TNF-alpha versus membrane bound TNF-alpha), the receptor (TNF-R1 versus TNF-R2) and the downstream signaling cascades utilized. The elucidation of the specific characteristics of TNF-signaling in distinct inflammatory disorders will lead to a better understanding ot the pathogenesis of these diseases and will be the basis for the development of more specific and more efficient therapeutic approaches.

Crohn Disease↗
PubMed2003

A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.

TH1 cytokines have been suggested to contribute to the pathogenesis of T-cell-mediated liver injury and inflammation. However, the molecular signaling pathways involved in such injury are still poorly understood. In the present study, we investigated the role of the STAT1/T-bet signaling pathway in a murine model of T-cell-mediated liver inflammation induced by the application of concanavalin A (Con A) using newly created STAT1 transgenic mice as well as STAT1- and T-bet-deficient mice. Liver injury induced by Con A was associated with an increase of both pSTAT1 and T-bet levels in the liver. Furthermore, functional studies suggested a pathogenic role for STAT1 in Con A-induced liver injury, because transgenic mice overexpressing STAT1 under the control of the CD2 promoter/enhancer construct showed elevated interferon gamma (IFN-gamma) and IRF-1 levels as well as significantly augmented liver injury following administration of Con A. Consistently, we observed that both STAT1-deficient and T-bet-deficient mice were protected from such T-cell-dependent liver injury. In conclusion, these findings suggest a key pathogenic role for the STAT1/T-bet signaling pathway for T-cell activation in the Con A model of T-cell-mediated liver pathology.

Animals↗
PubMed2003

Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.

BACKGROUND & AIMS: Timely diagnosis of intraepithelial neoplasias (IN) and colitis-associated colon carcinomas (CRC) is crucially important for the treatment of ulcerative colitis (UC). We performed a randomized, controlled trial to test whether chromoendoscopy (CE) might facilitate early detection of IN and CRC in UC. METHODS: A total of 263 patients with long-standing UC (>or=8 years) were screened for potential inclusion in the study, 165 of whom were randomized at a 1:1 ratio to undergo conventional colonoscopy or colonoscopy with CE using 0.1% methylene blue. Five mucosal biopsy specimens were taken every 10 cm between the rectum and cecum. Circumscript lesions in the colon were evaluated according to a modified pit pattern classification. RESULTS: In the CE group, there was a significantly better correlation between the endoscopic assessment of degree (P = 0.0002) and extent (89% vs. 52%; P < 0.0001) of colonic inflammation and the histopathologic findings compared with the conventional colonoscopy group. More targeted biopsies were possible, and significantly more IN were detected in the CE group (32 vs. 10; P = 0.003). Using the modified pit pattern classification, both the sensitivity and specificity for differentiation between non-neoplastic and neoplastic lesions were 93%. CONCLUSIONS: Based on our prospective randomized trial, CE permits more accurate diagnosis of the extent and severity of the inflammatory activity in UC compared with conventional colonoscopy. In addition, CE with methylene blue is a novel tool for the early detection of IN and CRC in patients with UC. These findings have important implications for medical and surgical interventions.

Adult↗
PubMed2003

Mucosal T cells: mediators or guardians of inflammatory bowel disease?

Because the mucosal immune system is continuously exposed to a myriad of potentially harmful environmental antigens, it frequently reacts with antiinflammatory/regulatory T cell responses driven by TGF-beta-producing TH3 cells and IL-10-producing regulatory T cells. Intestinal inflammation in patients with inflammatory bowel diseases is thought to result from an overwhelming uncontrolled activation of the mucosal immune system induced by antigens of the normal luminal flora in genetically susceptible individuals. Inflammatory bowel disease appears to be mediated by subsets of CD4 T lymphocytes or NK T cells secreting high levels of proinflammatory cytokines such as TNF-alpha. The increased expression of integrins/addressins in the inflamed gut and the increased expression of adhesion molecules on T cells facilitate migration of these pathogenic T cell subsets into the lamina propria. Additionally, the local activation of antiapoptotic pathways in pathogenic T lymphocytes leads to a further accumulation of these cells in the lamina propria, causing perpetuation and chronicity of inflammatory bowel disease. This concept is underlined by the finding that most potent immunosuppressive drugs used in treatment of inflammatory bowel disease seem to work by inducing T cell apoptosis via inhibition of STAT-3 and NFkappaB-dependent antiapoptotic pathways. Taken together, distinct T cell subsets appear to act as mediators or guardians of inflammatory bowel disease, and thus they play a central role in controlling the delicate balance between proinflammatory and antiinflammatory immune responses in the gut.

Journal Article↗
PubMed2003

The role of signal transducers and activators of transcription in T inflammatory bowel diseases.

Signal transducers and activators of transcription (STAT) proteins are intracellular effector molecules of cytokine-modulated signaling. On the one hand, they play an important role in hematopoiesis and the development of the human immune system. STAT transcription factors are necessary for embryogenesis and the maintenance of the mammalian immune response. In the adult, STAT signaling is responsible for T-cell polarization toward interferon gamma-secreting Th1 T cells or interleukin 4-producing Th2 cells. On the other hand, these proteins are involved in the regulation of T-cell survival. STAT activation is strongly associated with tyrosine phosphorylation by tyrosine kinases, namely Jak1, Jak2, Jak3, and Tyk2. Counterregulatory mechanisms protecting from overwhelming STAT activation are represented by protein inhibitors of activated STATs and the SOCS family proteins. Because STAT proteins are key response elements of cytokine-induced T-cell activation, the characterization of STAT proteins is one step to elucidate disturbed T-cell function in inflammatory bowel disease. In particular, an activation of STAT-4 and STAT-3 in T cells seems to play a key pathogenic role in Crohn's disease.

Cell Survival↗
PubMed2003

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

Adult↗
PubMed2003

Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells.

IL-12 p40-related cytokines such as IL-12 p35/p40 heterodimer and IL-23 (p19/p40) are potent regulators of adaptive immune responses. Little is known, however, about the transcriptional regulation of the p40 gene in vivo. In an attempt toward this goal, we have generated transgenic mice expressing firefly luciferase under the control of the IL-12 p40 promoter. High constitutive transgene expression was found in the small intestine only, whereas little reporter gene activity was observed in other tissues. Within the small bowel, constitutive promoter activity was restricted to the terminal ileum and associated with high expression of p40 mRNA as well as p40 and IL-23 p19/p40 proteins. The cells constitutively producing IL-12 p40 were identified as CD8alpha and CD11b double-negative CD11c+ lamina propria dendritic cells (LPDCs) that represent a major cell population in the lamina propria of the small intestine, but not in the colon. FISH directly demonstrated the uptake of bacteria by a subset of LPDCs in the terminal ileum that was associated with p40 expression. Furthermore, little or no p40 protein expression in LPDCs was found in the terminal ileum of germfree mice, indicating a key role of the intestinal flora for constitutive p40 expression. In addition, analysis of transgenic mice with a mutated NF-kappaB target site in the p40 promoter showed a critical role of NF-kappaB for constitutive transgene expression. Our data reveal important functional differences between the mucosal immune systems of the small and large bowel in healthy mice and suggest that the high bacterial load in the terminal ileum activates p40 gene transcription in LPDCs through NF-kappaB. These data suggest a predisposition of the terminal ileum to develop chronic inflammatory responses through IL-23 and thus may provide a molecular explanation for the preferential clinical manifestation of Crohn disease in this part of the gut.

Animals↗
PubMed2003

Inflammatory bowel disorders: gene therapy solutions.

Current options to treat inflammatory bowel diseases (IBDs) are often associated with undesired side effects, have limited therapeutic benefit for many patients and do not lead to a complete restoration of the mucosal immune balance. Recent research progress in the pathogenesis of IBDs has widely broadened our understanding of the complex nature of these immunological disorders and identified new potential therapeutic targets. New insights into the molecular mechanisms underlying IBDs may now allow the development of new in vivo or ex vivo therapeutic gene treatment strategies that alter the biological functions of cells in the inflamed gastrointestinal tract. New gene transfer approaches based either on blocking pro-inflammatory cytokines or overexpression of anti-inflammatory cytokines, particularly interleukin-10, showed promising results in animal models of IBD. Future studies analyzing the effects of cytokine-targeted gene therapy in patients are eagerly awaited.

Cytokines↗
PubMed2002

Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice.

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an alpha-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast to IFN-gamma production, which was only transiently decreased under such stimulation. Notably, EBI3-/- mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function.

Animals↗