14 results on '"Varga, Georg"'
Search Results
2. Spontaneous onset of TNFα‐triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H‐2 haplotype.
- Author
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Leite Dantas, Rafael, Bettenworth, Dominik, Varga, Georg, Weinhage, Toni, Wami, Haleluya Tesfaye, Dobrindt, Ulrich, Roth, Johannes, Vogl, Thomas, Ludwig, Stephan, and Wixler, Viktor
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T cells ,TUMOR necrosis factors ,B cells ,MAJOR histocompatibility complex ,INFLAMMATORY bowel diseases - Abstract
Recently, we established a doxycycline‐inducible human tumor necrosis factor alpha (TNFα)‐transgenic mouse line, ihTNFtg. Non‐induced young and elderly mice showed low but constitutive expression of hTNFα due to promoter leakiness. The persistently present hTNFα stimulated endogenous pro‐inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFα. The continuous upregulation of pro‐inflammatory mTNFα and mS100A8/A9 proteins, due to their mutual expression dependency, gradually led to increased levels in colon tissue and blood. This finally exceeded the threshold levels tolerated by the healthy organism, leading to the onset of intestinal inflammation. Here, recombinant hTNFα functioned as an initial trigger for the development of chronic inflammation. Crossing ihTNFtg mice with S100A9KO mice lacking active S100A8/A9 alarmins or with Rag1KO mice lacking T and B lymphocytes completely abrogated the development of colonic inflammation, despite the still leaky hTNFα promoter. Furthermore, both the intensity of the immune response and the strength of immunosuppressive Treg induction was found to depend on the major histocompatibility complex (MHC) genetic composition. In summary, the onset of intestinal inflammation in elderly mice depends on at least four factors that have to be present simultaneously: TNFα upregulation, S100A8/A9 protein expression, functional T lymphocytes and genetic composition, with the MHC haplotype being of central importance. Only joint action of these factors leads to chronic intestinal inflammation, while absence of any of these determinants abrogates the development of the autoimmune disorder. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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3. Macrophage-mediated psoriasis can be suppressed by regulatory T lymphocytes.
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Leite Dantas, Rafael, Masemann, Dörthe, Schied, Tanja, Bergmeier, Vera, Vogl, Thomas, Loser, Karin, Brachvogel, Bent, Varga, Georg, Ludwig, Stephan, and Wixler, Viktor
- Abstract
We recently described an inducible human TNF transgenic mouse line ( ihTNFtg) that develops psoriasis-like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro-inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF-mediated psoriasis, ihTNFtg mice were crossbred into RAG1
KO mice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1KO or wild-type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild-type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3-positive cells into RAG1KO or wild-type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro-inflammatory activity of macrophages, which are the major immune effector cells in hTNF-mediated psoriasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2016
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4. Activation-dependent cell death of human monocytes is a novel mechanism of fine-tuning inflammation and autoimmunity.
- Author
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Däbritz, Jan, Weinhage, Toni, Varga, Georg, Wirth, Timo, Ehrchen, Jan M., Barczyk‐Kahlert, Katarzyna, Roth, Johannes, Schwarz, Tobias, and Foell, Dirk
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In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA. [ABSTRACT FROM AUTHOR]
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- 2016
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5. MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection.
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Köther, Katharina, Nordhoff, Carolin, Masemann, Dörthe, Varga, Georg, Bream, Jay H., Gaestel, Matthias, Wixler, Viktor, and Ludwig, Stephan
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KINASES ,GENE expression ,KILLER cells ,T cells ,H5N1 Influenza - Abstract
MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Aft-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γ promoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3
-/- mice challenged with the Thl-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3-/- mice was accompanied by a > 10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2014
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6. Epidermal expression of I-TAC (Cxclll) instructs adaptive Th2-type immunity.
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Roebrock, Kirsten, Sunderkötter, Cord, Münck, Niels-Arne, Wolf, Marc, Nippe, Nadine, Barczyk, Katarzyna, Varga, Georg, Vogl, Thomas, Roth, Johannes, and Ehrchen, Jan
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IMMUNE system ,LEISHMANIA ,CHEMOKINES ,LABORATORY mice ,MUSCLE physiology ,LYMPH nodes - Abstract
To decipher early promoters of the local microenvironment for Th2-type immunity, we wanted to identify gene patterns that were induced by Leishmania major in the infected skin of susceptible, Th2-prone BALB/c, but not of resistant, Thl-prone C57BL/6 mice. We found a marked up-regulation of the chemokine I-TAC (Cxclll) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. Accordingly, local injection of I-TAC (2x1 |xg) in resistant mice on the first day of infection resulted in a Th2-driven, sustained deterioration of disease and dramatically enhanced parasite levels. On the cellular level, I-TAC decreased IL-12 production by dendritic cells (DCs) in skindraining lymph nodes and by DCs in vitro. Thus, we demonstrate for the first time that epidermis-derived I-TAC triggers a sustained Th2-response that determines the outcome of a complex immunological process. [ABSTRACT FROM AUTHOR]
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- 2014
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7. Expression of S100A8/A9 in HaCaT keratinocytes alters the rate of cell proliferation and differentiation
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Voss, Andreas, Bode, Günther, Sopalla, Claudia, Benedyk, Malgorzata, Varga, Georg, Böhm, Markus, Nacken, Wolfgang, and Kerkhoff, Claus
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GENE expression ,KERATINOCYTES ,CELL proliferation ,CELL differentiation ,ARACHIDONIC acid ,REACTIVE oxygen species ,NF-kappa B ,EPITHELIAL cells - Abstract
Abstract: S100A8/A9 promotes NADPH oxidase in HaCaT keratinocytes and subsequently increases NFκB activation, which plays important roles in the balance between epidermal growth and differentiation. S100A8/A9-positive HaCaT cells present with a significantly reduced rate of cell division and greater expression of two keratinocyte differentiation markers, involucrin and filaggrin, than control cells. S100A8/A9 mutants fail to enhance NFκB activation, TNFα-induced IL-8 gene expression and NFκB p65 phosphorylation, and S100A8/A9-positive cells demonstrate better cell survival in forced suspension culture than mutant cells. S100A8/A9 is induced in epithelial cells in response to stress. Therefore, S100A8/A9-mediated growth arrest could have implications for tissue remodeling and repair. [ABSTRACT FROM AUTHOR]
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- 2011
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8. β2 Integrin deficiency yields unconventional double-negative T cells distinct from mature classical natural killer T cells in mice.
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Oreshkova, Tsvetelina, Wang, Honglin, Seier, Anne M., Sindrilaru, Anca, Varga, Georg, Grabbe, Stephan, Scharffetter-Kochanek, Karin, and Peters, Thorsten
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GENE expression ,LEUCOCYTES ,T cells ,KILLER cells ,LABORATORY mice - Abstract
Expressed on leucocytes, β
2 integrins (CD11/CD18) are specifically involved in leucocyte function. Using a CD18-deficient (CD18−/− ) mouse model, we here report on their physiological role in lymphocyte differentiation and trafficking. CD18−/− mice present with a defect in the distribution of lymphocytes with highly reduced numbers of naïve B and T lymphocytes in inguinal and axillary lymph nodes. In contrast, cervical lymph nodes were fourfold enlarged harbouring unconventional T-cell receptor-αβ (TCR-αβ) and TCR-γδ CD3+ CD4− CD8− (double-negative; DN) T cells that expanded in situ. Using adoptive transfer experiments, we found that these cells did not home to peripheral lymph nodes of CD18wt recipients but, like antigen-experienced T or natural killer (NK) T cells, recirculated through non-lymphoid organs. Lacking regulatory functions in vitro, CD18−/− TCR-αβ DN T cells did not suppress the proliferation of polyclonally activated CD4+ or CD8+ (single-positive; SP) T cells. Most interestingly, CD18−/− TCR-αβ DN T cells showed intermediate TCR expression levels, an absent activation through allogeneic major histocompatibility complex and a strong proliferative dependence on interleukin-2, hence, closely resembling NKT cells. However, our data oppose former reports, clearly showing that, because of an absent reactivity with CD1d-αGalCer dimers, these cells are not mature classical NKT cells. Our data indicate that CD18−/− TCR-αβ DN T cells, like NKT and TCR-γδ T cells, share characteristics of both adaptive and innate immune cells, and may accumulate as a compensatory mechanism to the functional defect of adaptive immunity in CD18−/− mice. [ABSTRACT FROM AUTHOR]- Published
- 2009
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9. Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major.
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Ehrchen, Jan, Helming, Laura, Varga, Georg, Pasche, Bastian, Loser, Karin, Gunzer, Matthias, Sunderkötter, Cord, Sorg, Clemens, Roth, Johannes, and Lengeling, Andreas
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VITAMIN D ,INFECTION ,LEISHMANIA ,MACROPHAGES ,NITRIC oxide ,MICE - Abstract
We have previously reported that 1α,25-dihydroxyvitamin D
3 (1α,25(OH)2 D3 ) can selectively suppress key functions of interferon-gamma (IFN-γ) activated macrophages. To further explore this mechanism for its relevance in vivo, we investigated an infection model that crucially depends on the function of IFN-γ activated macrophages, the infection with the intracellular protozoan Leishmania major, 1α,25(OH)2 D3 treatment of L. major infected macrophages demonstrated a vitamin D receptor (Vdr) dependent inhibition of macrophage killing activity. Further analysis showed that this was a result of decreased production of nitric oxide by 1α,25(OH)2 D3 -treated macrophages due to Vdr-dependent up-regulation of arginase 1 expression, which overrides NO production by Nos2. When analyzing the course of infection in vivo, we found that Vdr-knockout (Vdr-KO) mice were more resistant to L. major infection than their wild-type littermates. This result is in agreement with an inhibitory influence of 1α,25(OH)2 D3 on the macrophage mediated host defense. Further investigation showed that Vdr-KO mice developed an unaltered T helper cell type 1 (Thl) response on infection as indicated by normal production of IFN-γ by CD4+ and CD8+ T cells. Therefore, we propose that the absence of 1α,25(OH)2 D3 -mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection. [ABSTRACT FROM AUTHOR]- Published
- 2007
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10. Structure and duration of contact between dendritic cells and T cells are controlled by T cell activation state.
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Rothoeft, Tobias, Balkow, Sandra, Krummen, Mathias, Beissert, Stefan, Varga, Georg, Loser, Karin, Oberbanscheidt, Pia, van den Boom, Frank, and Grabbe, Stephan
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- 2006
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11. Migration of immature mouse DC across resting endothelium is mediated by ICAM-2 but independent of β.
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Wethmar, Klaus, Helmus, Yvonne, Lühn, Kerstin, Jones, Claire, Laskowska, Anna, Varga, Georg, Grabbe, Stephan, Lyck, Ruth, Engelhardt, Britta, Bixel, M. Gabriele, Butz, Stefan, Loser, Karin, Beissert, Stefan, Ipe, Ute, Vestweber, Dietmar, and Wild, Martin K.
- Abstract
Immature dendritic cells (DC) reside in tissues where they initiate immune responses by taking up foreign antigens. Since DC have a limited tissue half-life, the DC pool in tissues has to be replenished constantly. This implies that precursor/immature DC must be able to cross non-activated endothelium using as yet unknown mechanisms. Here we show that immature, but not mature bone marrow-derived murine DC migrate across resting endothelial monolayers in vitro. We find that endothelial intercellular adhesion molecule-2 (ICAM-2) is a major player in transendothelial migration (TEM) of immature DC, accounting for at least 41% of TEM. Surprisingly, the ICAM-2-mediated TEM was independent of β-integrins, the known ICAM-2 ligands, since neither blocking of β-integrins with antibodies nor the use of CD18-deficient DC affected the ICAM-2-specific TEM. In humans, the C-type lectin DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) was shown to interact with ICAM-2, suggesting a similar role in mice. However, we find that none of the murine DC-SIGN homologues mDC-SIGN, murine DC-SIGN-related molecule-1 (mSIGN-R1) and mSIGN-R3 is expressed on the surface of bone marrow-derived mouse DC. Taken together, this study shows that ICAM-2 strongly supports transmigration of immature DC across resting endothelium by interacting with ligands that are distinct from β-integrins and DC-SIGN homologues. [ABSTRACT FROM AUTHOR]
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- 2006
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12. Effect of pimecrolimus vs. corticosteroids on murine bone marrow-derived dendritic cell differentiation, maturation and function.
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Krummen, Mathias B. W., Varga, Georg, Steinert, Meike, Stuetz, Anton, Luger, Thomas A., and Grabbe, Stephan
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NONSTEROIDAL anti-inflammatory agents , *SKIN inflammation , *CORTICOSTEROIDS , *DENDRITIC cells , *BONE marrow , *THERAPEUTICS - Abstract
Pimecrolimus (SDZ ASM981) is a non-steroid member of calcineurin inhibitors recently developed for the treatment of inflammatory skin diseases. In this study, we compared the effect of pimecrolimus and corticosteroids on the differentiation, maturation and function of murine bone marrow-derived dendritic cells (BM-DC). We added pimecrolimus at concentrations of 5–500 ng/ml or 0.5 ng/ml mometasone furoate at different timepoints to the BM-DC culture and checked (i) the number of matured cells, (ii) the expression of activation markers, (iii) the release of cytokines and (iv) the stimulatory capacity of the resulting BM-DC in vivo. Even at the highest concentration, pimecrolimus treatment resulted in only modest effects. In the pimecrolimus-treated culture, we observed a decrease in the numbers of matured cells but no significant effects on the expression of activation markers. The release of some inflammatory cytokines was reduced, but the stimulatory capacity in vivo was not affected. In contrast, mometasone furoate has pronounced effects on BM-DC at a concentration ten to 1000 times lower than those used with pimecrolimus. Furthermore, topical treatment of mice with clobetasole cream 0.05% resulted in almost complete depletion of splenic DC and a severe hyposplenia, while high-dose oral pimecrolimus treatment did not show any effects on the spleen or on splenic DC. These results support that pimecrolimus, unlike corticosteroids, has little effects on dendritic cells. To the best of our knowledge, this is the first study of this type with use of BM-DC. [ABSTRACT FROM AUTHOR]
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- 2006
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13. Enhanced contact hypersensitivity and antiviral immune responses in vivo by keratinocyte-targeted overexpression of IL-15.
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Loser, Karin, Mehling, Annette, Apelt, Jenny, Ständer, Sonja, Andres, Pietro G., Reinecker, Hans-Christian, Eing, Bodo R., Skryabin, Boris V., Varga, Georg, Schwarz, Thomas, and Beissert, Stefan
- Abstract
IL-15 is involved in lymphocyte homeostasis. To investigate the role of IL-15 in the skin in vivo, mice were generated that overexpress IL-15 in keratinocytes, resulting in increased IL-15 protein levels in the skin but not elevated IL-15 serum concentrations. Keratin 14 (K14)-IL-15 transgenic (tg) mice showed increased contact hypersensitivity (CHS) responses. Transfer of primed wild-type (wt) and tg T cells into naive wt or tg recipients indicated that skin-derived IL-15 enhanced the induction but not the elicitation phase of CHS. Tg mice could be sensitized even by suboptimal hapten concentrations. Accordingly, Langerhans cells (LC) from tg skin were identified as potent allostimulators, suggesting the involvement of IL-15-stimulated LC in the induction of adaptive immunity. Overexpression of IL-15 also strengthened innate immunity since tg mice infected with human HSV type I developed significantly smaller HSV skin lesions. In addition, tg mice resisted re-infection with HSV more effectively than wt mice did, which was associated with an elevated anti-HSV Ab production. Accordingly, injection of serum from re-infected tg mice protected naive recipients significantly from epicutaneous HSV infection, indicating that anti-HSV Ab produced by tg mice play an important role in resistance in vivo. Together, our results show that overexpression of IL-15 in the epidermis enhances both innate and adaptive cutaneous immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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14. Regulation by Rho family GTPases of IL-1 receptor induced signaling: C3-like chimeric toxin and Clostridium difficile toxin B inhibit signaling pathways involved in IL-2 gene expression.
- Author
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Dreikhausen, Ursula, Varga, Georg, Hofmann, Fred, Barth, Holger, Aktories, Klaus, Resch, Klaus, and Szamel, Marta
- Published
- 2001
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