2024-03-29T02:16:36Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/86172019-08-30T11:32:39Zcom_10033_6804com_10033_6799col_10033_6883
Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells
Satyanarayana, A.
Wiemann, S.U.
Buer, J.
Lauber, J.
Dittmar, K.E.J.
Wüstefeld, T.
Blasco, M.A.
Manns, M.P.
Rudolph, K.L.
2003-08-01
2007-02-20T13:12:00Z
2003-08-01
2007-02-20T13:12:00Z
2003-08-01
2007-02-20T13:12:00Z
2003-08-01
The EMBO Journal 2003 22(15):4003-4013
0261-4189
1460-2075
12881434
10.1093/emboj/cdg367
http://hdl.handle.net/10033/8617
169040
en_US
http://www.emboj.oupjournals.org/content/vol22/issue15/
Copyright © 2003 European Molecular Biology Organization
Oxford University Press
oai:repository.helmholtz-hzi.de:10033/86672019-08-30T11:27:08Zcom_10033_6804com_10033_6799col_10033_6883
Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling
Satyanarayana, A.
Greenberg, R. A.
Schaetzlein, S.
Buer, J.
Masutomi, K.
Hahn, W. C.
Zimmermann, S.
Martens, U.
Manns, M. P.
Rudolph, K. L.
2004-06
2007-02-20T14:38:00Z
2004-06
2007-02-20T14:38:00Z
2004-06
2007-02-20T14:38:00Z
2004-06
Molecular and Cellular Biology 2004 24(12):5459-5474
0270-7306
1098-5549
15169907
10.1128/MCB.24.12.5459-5474.2004
http://hdl.handle.net/10033/8667
419883
en_US
Copyright © 2004, American Society for Microbiology
American Society for Microbiology
oai:repository.helmholtz-hzi.de:10033/86972019-08-30T11:24:27Zcom_10033_6804com_10033_6799col_10033_6883
Skp2-dependent degradation of p27kip1 is essential for cell cycle progression
Kossatz, Uta
Dietrich, Nils
Zender, Lars
Buer, Jan
Manns, Michael P
Malek, Nisar P.
2004-11-01
2007-02-21T08:37:01Z
2004-11-01
2007-02-21T08:37:01Z
2004-11-01
2007-02-21T08:37:01Z
2004-11-01
Genes & Development 2004 18(21):2602-2607
0890-9369
15520280
10.1101/gad.321004
http://hdl.handle.net/10033/8697
525540
en_US
Copyright © 2004, Cold Spring Harbor Laboratory Press
Cold Spring Harbor Laboratory Press
oai:repository.helmholtz-hzi.de:10033/87052019-08-30T11:25:07Zcom_10033_6804com_10033_6799col_10033_6883
Common and Unique Gene Expression Signatures of Human Macrophages in Response to Four Strains of Mycobacterium avium That Differ in Their Growth and Persistence Characteristics
Blumenthal, Antje
Lauber, Jörg
Hoffmann, Reinhard
Ernst, Martin
Keller, Christine
Buer, Jan
Ehlers, Stefan
Reiling, Norbert
2005-06
2007-02-21T08:45:00Z
2005-06
2007-02-21T08:45:00Z
2005-06
2007-02-21T08:45:00Z
2005-06
Infection and Immunity 2005 73(6):3330-3341
0019-9567
1098-5522
15908359
10.1128/IAI.73.6.3330-3341.2005
http://hdl.handle.net/10033/8705
1111816
en_US
Copyright © 2005, American Society for Microbiology
American Society for Microbiology
oai:repository.helmholtz-hzi.de:10033/123682019-08-30T11:37:00Zcom_10033_6804com_10033_6799col_10033_6883
Identification of novel regulators in T-cell differentiation of aplastic anemia patients.
Franzke, Anke
Geffers, Robert
Hunger, J Katrin
Pförtner, Susanne
Piao, Wenji
Ivanyi, Philipp
Grosse, Jens
Probst-Kepper, Michael
Ganser, Arnold
Buer, Jan
BACKGROUND: Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. RESULTS: Among more than 22,200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response. CONCLUSION: Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.
2007-06-14T12:13:49Z
2007-06-14T12:13:49Z
2007-06-14T12:13:49Z
2006
Article
BMC Genomics 2006, 7:263
1471-2164
17052335
10.1186/1471-2164-7-263
http://hdl.handle.net/10033/12368
en
oai:repository.helmholtz-hzi.de:10033/128582019-08-30T11:24:31Zcom_10033_6804com_10033_6799col_10033_6883
CD8(+) T cells armed with retrovirally transduced IFN-gamma.
Becker, Christian
Lienenklaus, Stefan
Jablonska, Jadwiga
Bauer, Heike
Weiss, Siegfried
Interferon-gamma (IFN-gamma) is considered a key cytokine involved in the preventive and defensive responses of T cells against infectious pathogens and tumors. Therefore, the transgenic expression of IFN-gamma in specific T cells appears to be an obvious therapeutic possibility. To directly examine whether IFN-gamma production can be increased in T cells, we introduced an IFN-gamma encoding cDNA into IFN-gamma(-/-) and IFN-gamma(+/+) CD8(+) effector populations by retroviral transduction. Here, we show that CD8 T cells can be equipped with IFN-gamma that increases their capacity to secrete the cytokine. Despite constitutive retroviral IFN-gamma mRNA transcription, translation and secretion of IFN-gamma protein was tightly regulated and only observed in activated T cells. Neither proliferation nor cytolytic activity of CTL was affected by IFN-gamma transduction. Importantly, CD8(+) T cells retrovirally transduced with IFN-gamma exhibit augmented tumor suppressive capacity upon adoptive transfer into IFN-gamma(-/-) mice. Thus, T cells can be readily armed with IFN-gamma without risking immunopathology by dysregulated production of this highly potent proinflammatory cytokine.
2007-07-23T11:38:53Z
2007-07-23T11:38:53Z
2007-07-23T11:38:53Z
2007-01-01
Article
J. Mol. Med. 2007, 85(1):63-73
0946-2716
17109130
10.1007/s00109-006-0107-8
http://hdl.handle.net/10033/12858
en
oai:repository.helmholtz-hzi.de:10033/145442019-08-30T11:33:57Zcom_10033_6804com_10033_6799col_10033_6883
Signatures of human regulatory T cells: an encounter with old friends and new players.
Pfoertner, Susanne
Jeron, Andreas
Probst-Kepper, Michael
Guzman, Carlos A
Hansen, Wiebke
Westendorf, Astrid M
Toepfer, Tanja
Schrader, Andres J
Franzke, Anke
Buer, Jan
Geffers, Robert
BACKGROUND: Naturally occurring CD4+ CD25+ regulatory T cells (TReg) are involved in the control of autoimmune diseases, transplantation tolerance, and anti-tumor immunity. Thus far, genomic studies on TReg cells were restricted to murine systems, and requirements for their development, maintenance, and mode of action in humans are poorly defined. RESULTS: To improve characterization of human TReg cells, we compiled a unique microarray consisting of 350 TReg cell associated genes (Human TReg Chip) based on whole genome transcription data from human and mouse TReg cells. TReg cell specific gene signatures were created from 11 individual healthy donors. Statistical analysis identified 62 genes differentially expressed in TReg cells, emphasizing some cross-species differences between mice and humans. Among them, several 'old friends' (including FOXP3, CTLA4, and CCR7) that are known to be involved in TReg cell function were recovered. Strikingly, the vast majority of genes identified had not previously been associated with human TReg cells (including LGALS3, TIAF1, and TRAF1). Most of these 'new players' however, have been described in the pathogenesis of autoimmunity. Real-time RT-PCR of selected genes validated our microarray results. Pathway analysis was applied to extract signaling modules underlying human TReg cell function. CONCLUSION: The comprehensive set of genes reported here provides a defined starting point to unravel the unique characteristics of human TReg cells. The Human TReg Chip constructed and validated here is available to the scientific community and is a useful tool with which to study the molecular mechanisms that orchestrate TReg cells under physiologic and diseased conditions.
2007-11-13T12:06:04Z
2007-11-13T12:06:04Z
2007-11-13T12:06:04Z
2006
Article
Genome Biol. 2006, 7(7):R54
1465-6914
16836768
10.1186/gb-2006-7-7-r54
http://hdl.handle.net/10033/14544
en
oai:repository.helmholtz-hzi.de:10033/145462019-08-30T11:34:22Zcom_10033_6804com_10033_6799col_10033_6883
Multiple synergizing factors contribute to the strength of the CD8+ T cell response against listeriolysin O.
Bruder, Dunja
Nussbaum, Alexander K
Gakamsky, Dimitry M
Schirle, Markus
Stevanovic, Stefan
Singh-Jasuja, Harpreet
Darji, Ayub
Chakraborty, Trinad
Schild, Hansjörg
Pecht, Israel
Weiss, Siegfried
Immunodominance in CD8+ T cell responses against Listeria monocytogenes is a well-recognized but still not fully understood phenomenon. From listeriolysin, the major virulence factor of L. monocytogenes, only a single epitope, pLLO91-99, is presented by MHC class I molecules in BALB/c mice which dominates the cytotoxic T cell response against this bacterial pathogen. To obtain more insights into the molecular and cellular mechanisms underlying immunodominance of this particular epitope, we compared the various steps involved in the presentation and recognition of pLLO91-99 derived from a wild-type toxin with an equivalent epitope from a mutated toxin. This fully functional variant contains within the pLLO91-99 epitope a conservative isoleucine to alanine replacement at the C-terminal anchor residue which results in loss of antigenicity. The binding properties of the variant peptide to soluble Kd remained unaffected and cytotoxic T cells capable of recognizing the pLLO99A/Kd complex were detectable in BALB/c mice. However, such T cells required higher concentrations of antigen in order to be optimally activated in vitro. A comparison between the TAP translocation efficiency of wild-type and mutant peptide demonstrated that the mutation at the C-terminus leads to a reduced transportation rate. Furthermore, the amino acid substitution changes the in vitro proteasomal cleavage pattern, resulting in a reduced liberation of the correct peptide from a polypeptide precursor. Thus, in all assays employed the immunodominant epitope performs optimally while the variant was found to be inferior. The synergy of all these steps most likely is the decisive factor in the immunodominance of pLLO91-99.
2007-11-13T12:24:19Z
2007-11-13T12:24:19Z
2007-11-13T12:24:19Z
2006-01-01
Article
Int. Immunol. 2006, 18(1):89-100
0953-8178
16291651
10.1093/intimm/dxh352
http://hdl.handle.net/10033/14546
en
oai:repository.helmholtz-hzi.de:10033/153382019-08-30T11:31:49Zcom_10033_6804com_10033_6799col_10033_6883
Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.
Timmerbeul, Inke
Garrett-Engele, Carrie M
Kossatz, Uta
Chen, Xueyan
Firpo, Eduardo
Grünwald, Viktor
Kamino, Kenji
Wilkens, Ludwig
Lehmann, Ulrich
Buer, Jan
Geffers, Robert
Kubicka, Stefan
Manns, Michael P
Porter, Peggy L
Roberts, James M
Malek, Nisar P
Department of Gastroenterology, Hepatology, and Endocrinology, Institute for Molecular Biology, Department of Hematology and Oncology, Institute for Pathology, Hannover Medical School, D-30625 Hannover, Germany.
Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the SCFskp2 pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.
2007-12-17T15:22:03Z
2007-12-17T15:22:03Z
2007-12-17T15:22:03Z
2006-09-19
Article
Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. 2006, 103 (38):14009-14 Proc. Natl. Acad. Sci. U.S.A.
0027-8424
16966613
10.1073/pnas.0606316103
http://hdl.handle.net/10033/15338
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/159172019-08-30T11:35:39Zcom_10033_6804com_10033_6799col_10033_6883
Differential effect of auxotrophies on the release of macromolecules by Salmonella enterica vaccine strains.
Loessner, Holger
Endmann, Anne
Rohde, Manfred
Curtiss, Roy
Weiss, Siegfried
Molecular Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. holger.loessner@helmholtz-hzi.de
Attenuated Salmonella enterica strains have been widely used as live carriers for vaccines and therapeutic molecules. Appropriate attenuation has been introduced into such bacteria for safety reasons and the improvement of strain properties. Here, we compared two strains that were rendered auxotroph for diaminopimelic acid or thymidine monophosphate precursors by deletion of the genes asd or thyA, respectively. Upon removal of the complementing compound from bacterial cultures, both strains quickly lose their property to form colonies. However, while the Deltaasd bacteria lysed almost immediately under such conditions, DeltathyA bacteria remained physically intact during the observation period. As a consequence, the Deltaasd bacteria released their intracellular content such as proteins or plasmids into the supernatant. In contrast, no intracellular component, either proteins or plasmids, could be recovered from the supernatants of DeltathyA bacteria upon depletion of thymidine. Thus, the release of macromolecules from the bacterial carrier occurs as a consequence of appropriate lethal attenuation. This might substitute for sophisticated secretion systems.
2008-01-10T11:23:31Z
2008-01-10T11:23:31Z
2008-01-10T11:23:31Z
2006-12
Article
Differential effect of auxotrophies on the release of macromolecules by Salmonella enterica vaccine strains. 2006, 265 (1):81-8 FEMS Microbiol. Lett.
0378-1097
17034415
10.1111/j.1574-6968.2006.00470.x
http://hdl.handle.net/10033/15917
FEMS microbiology letters
en
oai:repository.helmholtz-hzi.de:10033/162762019-08-30T11:36:05Zcom_10033_6804com_10033_6799col_10033_6883
Impact of the rpoS genotype for acid resistance patterns of pathogenic and probiotic Escherichia coli.
Coldewey, Sina M
Hartmann, Maike
Schmidt, Dorothea S
Engelking, Uta
Ukena, Sya N
Gunzer, Florian
Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. sina.coldewey@web.de <sina.coldewey@web.de>
BACKGROUND: Enterohemorrhagic E. coli (EHEC), a subgroup of Shiga toxin (Stx) producing E. coli (STEC), may cause severe enteritis and hemolytic uremic syndrome (HUS) and is transmitted orally via contaminated foods or from person to person. The infectious dose is known to be very low, which requires most of the bacteria to survive the gastric acid barrier. Acid resistance therefore is an important mechanism of EHEC virulence. It should also be a relevant characteristic of E. coli strains used for therapeutic purposes such as the probiotic E. coli Nissle 1917 (EcN). In E. coli and related enteric bacteria it has been extensively demonstrated, that the alternative sigma factor sigmaS, encoded by the rpoS gene, acts as a master regulator mediating resistance to various environmental stress factors. METHODS: Using rpoS deletion mutants of a highly virulent EHEC O26:H11 patient isolate and the sequenced prototype EHEC EDL933 (ATCC 700927) of serotype O157:H7 we investigated the impact of a functional rpoS gene for orchestrating a satisfactory response to acid stress in these strains. We then functionally characterized rpoS of probiotic EcN and five rpoS genes selected from STEC isolates pre-investigated for acid resistance. RESULTS: First, we found out that ATCC isolate 700927 of EHEC EDL933 has a point mutation in rpoS, not present in the published sequence, leading to a premature stop codon. Moreover, to our surprise, one STEC strain as well as EcN was acid sensitive in our test environment, although their cloned rpoS genes could effectively complement acid sensitivity of an rpoS deletion mutant. CONCLUSION: The attenuation of sequenced EHEC EDL933 might be of importance for anyone planning to do either in vitro or in vivo studies with this prototype strain. Furthermore our data supports recently published observations, that individual E. coli isolates are able to significantly modulate their acid resistance phenotype independent of their rpoS genotype.
2008-01-17T14:24:19Z
2008-01-17T14:24:19Z
2008-01-17T14:24:19Z
2007
Article
Impact of the rpoS genotype for acid resistance patterns of pathogenic and probiotic Escherichia coli. 2007, 7:21 BMC Microbiol.
1471-2180
17386106
10.1186/1471-2180-7-21
http://hdl.handle.net/10033/16276
BMC microbiology
en
oai:repository.helmholtz-hzi.de:10033/191782019-08-30T11:36:32Zcom_10033_6804com_10033_6799col_10033_6883
Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.
Stecher, Bärbel
Robbiani, Riccardo
Walker, Alan W
Westendorf, Astrid M
Barthel, Manja
Kremer, Marcus
Chaffron, Samuel
Macpherson, Andrew J
Buer, Jan
Parkhill, Julian
Dougan, Gordon
von Mering, Christian
Hardt, Wolf-Dietrich
Institute of Microbiology, Swiss Institute of Technology Zurich, Zurich, Switzerland.
Most mucosal surfaces of the mammalian body are colonized by microbial communities ("microbiota"). A high density of commensal microbiota inhabits the intestine and shields from infection ("colonization resistance"). The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10(-/-), VILLIN-HA(CL4-CD8)) with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen.
2008-02-26T14:00:54Z
2008-02-26T14:00:54Z
2008-02-26T14:00:54Z
2007-10
Article
Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. 2007, 5 (10):2177-89 PLoS Biol.
1545-7885
17760501
10.1371/journal.pbio.0050244
http://hdl.handle.net/10033/19178
PLoS biology
en
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17760501
oai:repository.helmholtz-hzi.de:10033/251532019-08-30T11:26:42Zcom_10033_6804com_10033_6799col_10033_6883
Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination.
Trebst, Corinna
Heine, Sandra
Lienenklaus, Stefan
Lindner, Maren
Baumgärtner, Wolfgang
Weiss, Siegfried
Stangel, Martin
Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Interferon-beta (IFN-beta) is a pleiotropic cytokine that is known to modulate the immune response in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Spontaneous remyelination and repair mechanisms in MS are mostly insufficient and contribute to clinical disability. Here, we investigated whether IFN-beta has a potential in modifying the extent of de- and remyelination in a toxic model of CNS demyelination induced by the copper chelator cuprizone. IFN-beta deficient (k/o) mice showed an accelerated spontaneous remyelination. However, the amount of remyelination after 6 weeks did not differ between the two groups. Demyelination in IFN-beta k/o mice was paralleled by a diminished astrocytic and microglia response as compared with wildtype controls, whereas the accelerated remyelination was paralleled by an increased number of oligodendrocyte precursor cells (OPC) within the demyelinated lesion at the beginning of the remyelination phase. We hypothesize that the absence of IFN-beta leads to more efficient recruitment and proliferation of OPC already during demyelination, thus allowing early remyelination. These results demonstrate that IFN-beta is able to alter remyelination in the absence of an immune-mediated demyelination.
2008-05-08T14:10:16Z
2008-05-08T14:10:16Z
2008-05-08T14:10:16Z
2007-12
Article
Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination. 2007, 114 (6):587-96 Acta Neuropathol.
0001-6322
17940777
10.1007/s00401-007-0300-z
http://hdl.handle.net/10033/25153
Acta neuropathologica
en
oai:repository.helmholtz-hzi.de:10033/281522019-08-30T11:26:42Zcom_10033_6804com_10033_6799col_10033_6883
Sensitivity to Escherichia coli Nissle 1917 in mice is dependent on environment and genetic background.
Bleich, Andre
Sundberg, John P
Smoczek, Anna
von Wasielewski, Reinhard
de Buhr, Maike F
Janus, Lydia M
Julga, Gwen
Ukena, Sya N
Hedrich, Hans-J
Gunzer, Florian
Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany. bleich.andre@mh-hannover.de
Escherichia coli Nissle 1917 (EcN) is a well-characterized probiotic bacterium. Although genomic comparisons of EcN with the uropathogenic E. coli strain CFT073 revealed high degrees of similarity, EcN is generally considered a non-pathogenic organism. However, as recent evidence suggests that EcN is capable of inducing inflammatory responses in host intestinal epithelial cells, we aimed to investigate potential pathogenic properties of EcN in an in vivo model using various germ-free (GF) mouse strains. With the exception of C3H/HeJZtm mice, which carry a defective toll-like receptor (TLR)4-allele, no lesions were obvious in mice of different strains orally inoculated with EcN for 1 week, although organ cultures (blood, lung, mesenteric lymph node, pancreas, spleen, liver and kidney) tested positive to various degrees. C3H/HeJZtm mice inoculated with EcN became clinically ill and the majority died or had to be euthanized. Organs of all gnotobiotic C3H/HeJZtm mice were positive for EcN by culture; major histological findings were moderate to severe pyogranulomatous serositis, typhlitis and pancreatitis. Histological findings were corroborated by highly elevated tumour necrosis factor (TNF) serum levels. Lesions were not detected in specified pathogen free maintained C3H/HeJZtm mice, GF C3H/HeJ mice lacking the interleukin-10 gene, or GF C3H/HeJZtm mice that were inoculated with E. coli K12 strain MG1655 as a control. In addition, mild histological lesions were detected in Ztm:NMRI mice 3 months after oral inoculation with EcN. This study shows that EcN is capable of displaying a virulent phenotype in GF C3H/HeJZtm mice. Whether this phenotype is linked to the bacterium's probiotic nature should be the focus of further studies.
2008-05-26T13:15:34Z
2008-05-26T13:15:34Z
2008-05-26T13:15:34Z
2008-02
Article
Sensitivity to Escherichia coli Nissle 1917 in mice is dependent on environment and genetic background. 2008, 89 (1):45-54notInt J Exp Pathol
1365-2613
18005134
10.1111/j.1365-2613.2007.00560.x
http://hdl.handle.net/10033/28152
International journal of experimental pathology
en
oai:repository.helmholtz-hzi.de:10033/360522019-08-30T11:31:49Zcom_10033_6804com_10033_6799col_10033_6883
Hypermetabolic syndrome as a consequence of repeated psychological stress in mice.
Depke, Maren
Fusch, Gerhard
Domanska, Grazyna
Geffers, Robert
Völker, Uwe
Schuett, Christine
Kiank, Cornelia
Ernst-Moritz-Arndt-University, Interfaculty Institute of Genetics and Functional Genomics, 17487 Greifswald, Germany.
Stress is a powerful modulator of neuroendocrine, behavioral, and immunological functions. After 4.5-d repeated combined acoustic and restraint stress as a murine model of chronic psychological stress, severe metabolic dysregulations became detectable in female BALB/c mice. Stress-induced alterations of metabolic processes that were found in a hepatic mRNA expression profiling were verified by in vivo analyses. Repeatedly stressed mice developed a hypermetabolic syndrome with the severe loss of lean body mass, hyperglycemia, dyslipidemia, increased amino acid turnover, and acidosis. This was associated with hypercortisolism, hyperleptinemia, insulin resistance, and hypothyroidism. In contrast, after a single acute stress exposure, changes in expression of metabolic genes were much less pronounced and predominantly confined to gluconeogenesis, probably indicating that metabolic disturbances might be initiated already early but will only manifest in repeatedly stressed mice. Thus, in our murine model, repeated stress caused severe metabolic dysregulations, leading to a drastic reduction of the individual's energy reserves. Under such circumstances stress may further reduce the ability to cope with new stressors such as infection or cancer.
2008-08-21T09:28:28Z
2008-08-21T09:28:28Z
2008-08-21T09:28:28Z
2008-06
Article
Hypermetabolic syndrome as a consequence of repeated psychological stress in mice. 2008, 149 (6):2714-23 Endocrinology
0013-7227
18325986
10.1210/en.2008-0038
http://hdl.handle.net/10033/36052
Endocrinology
en
oai:repository.helmholtz-hzi.de:10033/872372019-08-30T11:35:14Zcom_10033_6804com_10033_6799col_10033_6883
Type I interferon drives tumor necrosis factor-induced lethal shock.
Huys, Liesbeth
Van Hauwermeiren, Filip
Dejager, Lien
Dejonckheere, Eline
Lienenklaus, Stefan
Weiss, Siegfried
Leclercq, Georges
Libert, Claude
Department for Molecular Biomedical Research, VIB, Ghent B9052, Belgium.
Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-alpha receptor 1 (IFNAR-1) or in IFN-beta are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1(-/-) mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1(-/-) mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element-dependent genes, many of which encode chemokines. In livers of IFNAR-1(-/-) mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.
2009-12-02T15:31:30Z
2009-12-02T15:31:30Z
2009-12-02T15:31:30Z
2009-08-31
Article
Type I interferon drives tumor necrosis factor-induced lethal shock. 2009, 206 (9):1873-82 J. Exp. Med.
1540-9538
19687227
10.1084/jem.20090213
http://hdl.handle.net/10033/87237
The Journal of experimental medicine
en
oai:repository.helmholtz-hzi.de:10033/941532019-08-30T11:35:13Zcom_10033_6804com_10033_6799col_10033_6883
Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity.
Ukena, Sya N
Singh, Anurag
Dringenberg, Ulrike
Engelhardt, Regina
Seidler, Ursula
Hansen, Wiebke
Bleich, André
Bruder, Dunja
Franzke, Anke
Rogler, Gerhard
Suerbaum, Sebastian
Buer, Jan
Gunzer, Florian
Westendorf, Astrid M
Department of Mucosal Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
BACKGROUND: Probiotics are proposed to positively modulate the intestinal epithelial barrier formed by intestinal epithelial cells (IECs) and intercellular junctions. Disruption of this border alters paracellular permeability and is a key mechanism for the development of enteric infections and inflammatory bowel diseases (IBDs). METHODOLOGY AND PRINCIPAL FINDINGS: To study the in vivo effect of probiotic Escherichia coli Nissle 1917 (EcN) on the stabilization of the intestinal barrier under healthy conditions, germfree mice were colonized with EcN or K12 E. coli strain MG1655. IECs were isolated and analyzed for gene and protein expression of the tight junction molecules ZO-1 and ZO-2. Then, in order to analyze beneficial effects of EcN under inflammatory conditions, the probiotic was orally administered to BALB/c mice with acute dextran sodium sulfate (DSS) induced colitis. Colonization of gnotobiotic mice with EcN resulted in an up-regulation of ZO-1 in IECs at both mRNA and protein levels. EcN administration to DSS-treated mice reduced the loss of body weight and colon shortening. In addition, infiltration of the colon with leukocytes was ameliorated in EcN inoculated mice. Acute DSS colitis did not result in an anion secretory defect, but abrogated the sodium absorptive function of the mucosa. Additionally, intestinal barrier function was severely affected as evidenced by a strong increase in the mucosal uptake of Evans blue in vivo. Concomitant administration of EcN to DSS treated animals resulted in a significant protection against intestinal barrier dysfunction and IECs isolated from these mice exhibited a more pronounced expression of ZO-1. CONCLUSION AND SIGNIFICANCE: This study convincingly demonstrates that probiotic EcN is able to mediate up-regulation of ZO-1 expression in murine IECs and confer protection from the DSS colitis-associated increase in mucosal permeability to luminal substances.
2010-03-12T09:20:52Z
2010-03-12T09:20:52Z
2010-03-12T09:20:52Z
2007
Article
Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. 2007, 2 (12):e1308 PLoS ONE
1932-6203
18074031
10.1371/journal.pone.0001308
http://hdl.handle.net/10033/94153
PloS one
en
oai:repository.helmholtz-hzi.de:10033/959752019-08-30T11:29:17Zcom_10033_6804com_10033_6799col_10033_6883
The host response to the probiotic Escherichia coli strain Nissle 1917: specific up-regulation of the proinflammatory chemokine MCP-1.
Ukena, Sya N
Westendorf, Astrid M
Hansen, Wiebke
Rohde, Manfred
Geffers, Robert
Coldewey, Sina
Suerbaum, Sebastian
Buer, Jan
Gunzer, Florian
German Research Centre for Biotechnology, Mucosal Immunity Group, Mascheroder Weg 1, 38124 Braunschweig, Germany. suk@gbf.de
BACKGROUND: The use of live microorganisms to influence positively the course of intestinal disorders such as infectious diarrhea or chronic inflammatory conditions has recently gained increasing interest as a therapeutic alternative. In vitro and in vivo investigations have demonstrated that probiotic-host eukaryotic cell interactions evoke a large number of responses potentially responsible for the effects of probiotics. The aim of this study was to improve our understanding of the E. coli Nissle 1917-host interaction by analyzing the gene expression pattern initiated by this probiotic in human intestinal epithelial cells. METHODS: Gene expression profiles of Caco-2 cells treated with E. coli Nissle 1917 were analyzed with microarrays. A second human intestinal cell line and also pieces of small intestine from BALB/c mice were used to confirm regulatory data of selected genes by real-time RT-PCR and cytometric bead array (CBA) to detect secretion of corresponding proteins. RESULTS: Whole genome expression analysis revealed 126 genes specifically regulated after treatment of confluent Caco-2 cells with E. coli Nissle 1917. Among others, expression of genes encoding the proinflammatory molecules monocyte chemoattractant protein-1 ligand 2 (MCP-1), macrophage inflammatory protein-2 alpha (MIP-2alpha) and macrophage inflammatory protein-2 beta (MIP-2beta) was increased up to 10 fold. Caco-2 cells cocultured with E. coli Nissle 1917 also secreted high amounts of MCP-1 protein. Elevated levels of MCP-1 and MIP-2alpha mRNA could be confirmed with Lovo cells. MCP-1 gene expression was also up-regulated in mouse intestinal tissue. CONCLUSION: Thus, probiotic E. coli Nissle 1917 specifically upregulates expression of proinflammatory genes and proteins in human and mouse intestinal epithelial cells.
2010-04-08T09:10:02Z
2010-04-08T09:10:02Z
2010-04-08T09:10:02Z
2005
Article
The host response to the probiotic Escherichia coli strain Nissle 1917: specific up-regulation of the proinflammatory chemokine MCP-1. 2005, 6:43 BMC Med. Genet.
1471-2350
16351713
10.1186/1471-2350-6-43
http://hdl.handle.net/10033/95975
BMC medical genetics
en
oai:repository.helmholtz-hzi.de:10033/965972019-08-30T11:34:48Zcom_10033_6804com_10033_6799col_10033_6883
Drug-inducible remote control of gene expression by probiotic Escherichia coli Nissle 1917 in intestine, tumor and gall bladder of mice.
Loessner, Holger
Leschner, Sara
Endmann, Anne
Westphal, Kathrin
Wolf, Kathrin
Kochruebe, Katja
Miloud, Tewfik
Altenbuchner, Josef
Weiss, Siegfried
Molecular Immunology, Helmholtz Centre for Infection Research, HZI, Inhoffenstrasse 7, 38124 Braunschweig, Germany. loeho@pei.de
The probiotic bacterium Escherichia coli Nissle 1917 (EcN) constitutes a prospective vector for delivering heterologous therapeutic molecules to treat several human disorders. To add versatility to this carrier system, bacteria should be equipped with expression modules that can be regulated deliberately in a temporal and quantitative manner. This approach is called in vivo remote control (IVRC) of bacterial vectors. Here, we have evaluated promoters P(araBAD), P(rhaBAD) and P(tet), which can be induced with L-arabinose, L-rhamnose or anhydrotetracycline, respectively. EcN harboring promoter constructs with luciferase as reporter gene were administered either orally to healthy mice or intravenously to tumor bearing animals. Subsequent to bacterial colonization of tissues, inducer substances were administered via the oral or systemic route. By use of in vivo bioluminescence imaging, the time course of reporter gene expression was analyzed. Each promoter displayed a specific in vivo induction profile depending on the niche of bacterial residence and the route of inducer administration. Importantly, we also observed colonization of gall bladders of mice when EcN was administered systemically at high doses. Bacteria in this anatomical compartment remained accessible to remote control of bacterial gene expression.
2010-04-15T12:06:20Z
2010-04-15T12:06:20Z
2010-04-15T12:06:20Z
2009-12
Article
Drug-inducible remote control of gene expression by probiotic Escherichia coli Nissle 1917 in intestine, tumor and gall bladder of mice. 2009, 11 (14-15):1097-105 Microbes Infect.
1769-714X
19665575
10.1016/j.micinf.2009.08.002
http://hdl.handle.net/10033/96597
Microbes and infection / Institut Pasteur
en