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Your search keyword '"Siegmund, Daniela"' showing total 202 results
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202 results on '"Siegmund, Daniela"'

4. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

Author

Cuchet-Lourenço, Delphine, Eletto, Davide, Wu, Changxin, Plagnol, Vincent, Papapietro, Olivier, Curtis, James, Ceron-Gutierrez, Lourdes, Bacon, Chris M., Hackett, Scott, Alsaleem, Badr, Maes, Mailis, Gaspar, Miguel, Alisaac, Ali, Goss, Emma, AlIdrissi, Eman, Siegmund, Daniela, Wajant, Harald, Kumararatne, Dinakantha, AlZahrani, Mofareh S., Arkwright, Peter D., Abinun, Mario, Doffinger, Rainer, and Nejentsev, Sergey

Published
2018

11. Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

Author

Chopra, Martin, Brandl, Andreas, Siegmund, Daniela, Mottok, Anja, Schäfer, Viktoria, Biehl, Marlene, Kraus, Sabrina, Bäuerlein, Carina A., Ritz, Miriam, Mattenheimer, Katharina, Schwinn, Stefanie, Seher, Axel, Grabinger, Thomas, Einsele, Hermann, Rosenwald, Andreas, Brunner, Thomas, Beilhack, Andreas, and Wajant, Harald

Published
2015
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22. Apoptosis is not required for acantholysis in pemphigus vulgaris

Author

Schmidt, Enno, Gutberlet, Judith, Siegmund, Daniela, Berg, Daniela, Wajant, Harald, and Waschke, Jens

Subjects
Apoptosis -- Research, Pemphigus -- Causes of, Pemphigus -- Research, Keratinocytes -- Physiological aspects, Keratinocytes -- Research, Biological sciences
Abstract

The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused primarily by autoantibodies against desmosomal cadherins. It was reported that apoptosis can be detected in pemphigus skin lesions and that apoptosis can be induced by PV-IgG in cultured keratinocytes. However, the role of apoptosis in PV pathogenesis is unclear at present. In this study, we provide evidence that apoptosis is not required for acantholysis in PV. In skin lesions from two PV patients, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positivity, but not cleaved caspase-3, was detected in single keratinocytes in some lesions but was completely absent in other lesions from the same patients. In cultures of human keratinocytes (HaCaT and normal human epidermal keratinocytes), PV-IgG from three different PV patients caused acantholysis, fragmented staining of Dsg 3 staining, and cytokeratin retraction in the absence of nuclear fragmentation, TUNEL positivity, and caspase-3 cleavage and hence in the absence of detectable apoptosis. To further rule out the contribution of apoptotic mechanisms, we used two different approaches that are effective to block apoptosis induced by various stimuli. Inhibition of caspases by z-VAD-fmk as well as overexpression of Fas-associated death domain-like interleukin-l[beta]-converting enzyme (FLICE)-like inhibitory proteins [FLIP.sub.L] and [FLIP.sub.S] to inhibit receptor-mediated apoptosis did not block PV-IgG-induced effects, indicating that apoptosis was not required. Taken together, we conclude that apoptosis is not a prerequisite for skin blistering in PV but may occur secondary to acantholysis. autoantibody; desmoglein 3; keratinocyte

Published
2009

31. TRAF2 Controls Death Receptor-Induced Caspase-8 Processing and Facilitates Proinflammatory Signaling

Author

Kreckel, Jennifer, Anany, Mohammed A., Siegmund, Daniela, and Wajant, Harald

Subjects
Immunology, Apoptosis, caspase-8, Cell Line, Cell Line, Tumor, death receptors, Humans, ddc:610, fas Receptor, TRAILR2, TRAILR1, Original Research, Inflammation, Caspase 8, Interleukin-8, NF-kappa B, Receptors, Death Domain, HCT116 Cells, TNF Receptor-Associated Factor 2, Up-Regulation, TNFR1, TRAF1, TRAF2, HEK293 Cells, Receptors, Tumor Necrosis Factor, Type I, CD95, Signal Transduction
Abstract

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.

Published
2019

32. TNFR1 and TNFR2 in the Control of the Life and Death Balance of Macrophages

Author

Wajant, Harald and Siegmund, Daniela

Subjects
TNFR1, ripk1, Cell and Developmental Biology, TNFR2, lcsh:Biology (General), apoptosis, TNF, necroptosis, ddc:610, Review, lcsh:QH301-705.5, ripk3, caspase-8
Abstract

Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling.

Published
2019

41. Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2.

Author

Siegmund, Daniela, Lang, Isabell, and Wajant, Harald

Subjects
*CELL death, *DEATH receptors, *GENETIC transcription, *CELLULAR signal transduction, *INFLAMMATION, *CANCER immunology, *PHYSIOLOGY
Abstract

Since their identification more than 20 years ago, the death receptors CD95, TRAILR1, and TRAILR2 have been intensively studied with respect to their cell death-inducing activities. These receptors, however, can also trigger a variety of cell death-independent cellular responses reaching from the activation of proinflammatory gene transcription programs over the stimulation of proliferation and differentiation to induction of cell migration. The cell death-inducing signaling mechanisms of CD95 and the TRAIL death receptors are well understood. In contrast, despite the increasing recognition of the biological and pathophysiological relevance of the cell death-independent activities of CD95, TRAILR1, and TRAILR2, the corresponding signaling mechanisms are less understood and give no fully coherent picture. This review is focused on the cell death-independent activities of CD95 and the TRAIL death receptors and addresses mainly three questions: (a) how are these receptors linked to noncell death pathways at the molecular level, (b) which factors determine the balance of cell death and cell death-independent activities of CD95 and the TRAIL death receptors at the cellular level, and (c) what are the consequences of the cell death-independent functions of these receptors for their role in cancer and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Published
2017
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42. Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

Author

Brunekreeft, Kim L, primary, Strohm, Corinna, additional, Gooden, Marloes J, additional, Rybczynska, Anna A, additional, Nijman, Hans W, additional, Grigoleit, Götz U, additional, Helfrich, Wijnand, additional, Bremer, Edwin, additional, Siegmund, Daniela, additional, Wajant, Harald, additional, and de Bruyn, Marco, additional

Published
2014
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44. Selective inhibition of FLICE-like inhibitory protein expression with small interfering RNA oligonucleotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis

Author

Siegmund, Daniela, Hadwiger, Philipp, Pfizenmaier, Klaus, Vornlocher, Hans-Peter, and Wajant, Harald

Subjects
Cell Survival, Blotting, Western, Green Fluorescent Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Oligonucleotides, Apoptosis, Ligands, Transfection, KB Cells, TNF-Related Apoptosis-Inducing Ligand, Humans, RNA, Messenger, RNA, Small Interfering, Cell Line, Transformed, Caspase 8, Membrane Glycoproteins, Tumor Necrosis Factor-alpha, Intracellular Signaling Peptides and Proteins, Ribonuclease, Pancreatic, Fibroblasts, Flow Cytometry, Caspase 9, Luminescent Proteins, Electroporation, Drug Resistance, Neoplasm, Caspases, Apoptosis Regulatory Proteins, Carrier Proteins, Research Article
Abstract

BACKGROUND: Most tumors express death receptors and their activation represents a potential selective approach in cancer treatment. The most promising candidate for tumor selective death receptor-activation is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L, which activates the death receptors TRAIL-R1 and TRAIL-R2, and induces apoptosis preferentially in tumor cells but not in normal tissues. However, many cancer cells are not or only moderately sensitive towards TRAIL and require cotreatment with irradiation or chemotherapy to yield a therapeutically reasonable apoptotic response. Because chemotherapy can have a broad range of unwanted side effects, more specific means for sensitizing tumor cells for TRAIL are desirable. The expression of the cellular FLICE-like inhibitory protein (cFLIP) is regarded as a major cause of TRAIL resistance. We therefore analyzed the usefulness of targeting FLIP to sensitize tumor cells for TRAIL-induced apoptosis. MATERIALS AND METHODS: To selectively interfere with expression of cFLIP short double-stranded RNA oligonucleotides (small interfering RNAs [siRNAs]) were introduced in the human cell lines SV80 and KB by electroporation. Effects of siRNA on FLIP expression were analyzed by Western blotting and RNase protection assay and correlated with TRAIL sensitivity upon stimulation with recombinant soluble TRAIL and TRAIL-R1- and TRAIL-R2-specific agonistic antibodies. RESULTS: FLIP expression can be inhibited by RNA interference using siRNAs, evident from reduced levels of FLIP-mRNA and FLIP protein. Inhibition of cFLIP expression sensitizes cells for apoptosis induction by TRAIL and other death ligands. In accordance with the presumed function of FLIP as an inhibitor of death receptor-induced caspase-8 activation, down-regulation of FLIP by siRNAs enhanced TRAIL-induced caspase-8 activation. CONCLUSION: Inhibition of FLIP expression was sufficient to sensitize tumor cells for TRAIL-induced apoptosis. The combination of TRAIL and FLIP-targeting siRNA could therefore be a useful strategy to attack cancer cells, which are resistant to TRAIL alone.

Published
2002

48. Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princepsluciferase antibody fusion proteins

Author

Kums, Juliane, Nelke, Johannes, Rüth, Benedikt, Schäfer, Viktoria, Siegmund, Daniela, and Wajant, Harald

Abstract

ABSTRACTCell surface antigen-specific antibodies are of substantial diagnostic and therapeutic importance. The binding properties of such antibodies are usually evaluated by cell-free assays, in particular surface plasmon resonance (SPR) analysis, or flow cytometry. SPR analyses allow the detailed quantitative and dynamic evaluation of the binding properties of antibodies, but need purified, typically recombinantly produced antigens. It can, however, be difficult to produce the required antigen. Furthermore, cellular factors influencing the antigen-antibody interaction are not considered by this method. Flow cytometry-based analyses do not have these limitations, but require elaborated calibration controls for absolute quantification of bound molecules. To overcome the limitations of SRP and flow cytometry in the characterization of cell surface antigen-specific antibodies, we developed Fn14-specific antibody 18D1 as an example of an antibody fusion protein format that includes the luciferase of Gaussia princeps(GpL), which enables very simple and highly sensitive cellular binding studies. We found that GpL-tagging of the C-terminus of the antibody light chain does not affect the interaction of 18D1-IgG1 with its antigen and Fc-gamma receptors (FcγRs). In accordance with this, the GpL(LC-CT)-18D1-IgG1 antibody fusion protein showed basically the same FcγR-dependent agonistic properties as the parental 18D1 antibody. Similar results were obtained with isotype switch variants of 18D1 and antibodies specific for CD95, LTβR and CD40. In sum, we demonstrate that antibody GpL fusion proteins are easily manageable and versatile tools for the characterization of cell surface antigen-antibody interactions that have the potential to considerably extend the instrumentarium for the evaluation of antibodies.

Published
2017
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50. Signaling Profile and Anti-Tumor Activity of the Novel HSP90 Inhibitor NVP-AUY922 in Multiple Myeloma.

Author

Stühmer, Thorsten, primary, Zöllinger, Angela, additional, Siegmund, Daniela, additional, Chatterjee, Manik, additional, Grella, Evelyn, additional, Knop, Stefan, additional, Kortüm, Martin, additional, Unzicker, Christian, additional, Jensen, Michael R., additional, Quadt, Cornelia, additional, Chène, Patrick, additional, Schoepfer, Joseph, additional, Garcia-Echeverria, Carlos, additional, Einsele, Herrmann, additional, Wajant, Harald, additional, and Bargou, Ralf C., additional

Published
2007
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