Bernhard Brüne

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

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Publications (294)1338.62 Total impact

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    ABSTRACT: Translating murine data to the human situation, we proposed that the level of PPAR[gamma] expression in T cells from septic patients correlates with clinical outcome. In this preliminary report we analyzed PPAR[gamma] mRNA expression in CD3+ T cells derived from blood of a very small number of septic patients (n = 18) on various days up to two weeks after the initial diagnosis. CD3+ T cell count was determined by flow cytometry. T cells from n = 11 healthy donors were included as controls. Maximal PPAR[gamma] mRNA expression was observed on the day of sepsis diagnosis (day 0; 5896 +/- 1523 copies PPAR[gamma] mRNA/25 ng mRNA, *p < 0.05 vs. controls). In contrast, the number of CD3+ T cells was significantly decreased in septic patients compared to healthy controls (296 +/- 31 vs. 1803 +/- 134 T cells/[mu]l blood, ***p < 0.001). Setting the arbitrary two limits: 1. patients with a PPAR[gamma] expression in T cells higher than 7.000 copies/25 ng mRNA, among whom five of six patients died during the ICU stay and 2. patients with a T cell count below 100 T cells/[mu]l blood, among whom five of eight patients died, identified a correlation between sepsis survival and low T cell number, paired with high T cell specific PPAR[gamma] expression. Among all 18 sepsis patients, four fulfilled the criteria for both arbitrary settings and all four of these patients subsequently died. We suggest that both high PPAR[gamma] expression in T cells and low absolute T cell number in blood of septic patients may have the potential as a new prognostic marker for a poor sepsis outcome.
    No preview · Article · Jan 2016 · Shock
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) produce large amounts of type I IFN in response to TLR7/9 ligands. This conveys antiviral effects, activates other immune cells (NK cells, conventional DCs, B, and T cells), and causes the induction and expansion of a strong inflammatory response. pDCs are key players in various type I IFN-driven autoimmune diseases such as systemic lupus erythematosus or psoriasis, but pDCs are also involved in (anti-)tumor immunity. The sphingolipid sphingosine-1-phosphate (S1P) signals through five G-protein-coupled receptors (S1PR1-5) to regulate, among other activities, immune cell migration and activation. The present study shows that S1P stimulation of human, primary pDCs substantially decreases IFN-α production after TLR7/9 activation with different types of CpG oligodeoxynucleotides or tick-borne encephalitis vaccine, which occurred in an S1PR4-dependent manner. Mechanistically, S1PR4 activation preserves the surface expression of the human pDC-specific inhibitory receptor Ig-like transcript 7. We provide novel information that Ig-like transcript 7 is rapidly internalized upon receptor-mediated endocytosis of TLR7/9 ligands to allow high IFN-α production. This is antagonized by S1PR4 signaling, thus decreasing TLR-induced IFN-α secretion. At a functional level, attenuated IFN-α production failed to alter Ag-driven T cell proliferation in pDC-dependent T cell activation assays, but shifted cytokine production of T cells from a Th1 (IFN-γ) to a regulatory (IL-10) profile. In conclusion, S1PR4 agonists block human pDC activation and may therefore be a promising tool to restrict pathogenic IFN-α production.
    No preview · Article · Jan 2016 · The Journal of Immunology
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    ABSTRACT: Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus and obesity. MetS patients are strongly exposed to polypharmacy, however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multi-target compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure activity relationship studies were performed on both targets, resulting in a sub-micromolar (sEH IC50 = 0.3 µM / PPARγ EC50 = 0.3 µM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long term animal models of MetS.
    Preview · Article · Nov 2015 · Journal of Medicinal Chemistry
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    Bernhard Brüne · Andreas Weigert · Nathalie Dehne
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    ABSTRACT: Tumor associated macrophages (TAMs) are known to support tumor progression and their accumulation is generally associated with poor prognosis. The shift from a tumor-attacking to a tumor-supportive macrophage phenotype is based on an educational program that, at least in part, is initiated by apoptotic tumor cells.
    Preview · Article · Aug 2015
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    ABSTRACT: Macrophages respond to the Th2 cytokine interleukin-4 (IL-4) with elevated expression of arachidonate 15-lipoxygenase (ALOX15). Although IL-4 signaling elicits anti-inflammatory responses, 15-lipoxygenase may either support or inhibit inflammatory processes in a context-dependent manner. AMP-activated protein kinase (AMPK) is a metabolic sensor/regulator that supports an anti-inflammatory macrophage phenotype. How AMPK-activation is linked to IL-4-elicited gene signatures remains unexplored. Using primary human macrophages stimulated with IL-4, we observed elevated ALOX15 mRNA and protein expression, which was attenuated by AMPK activation. AMPK activators, e.g. phenformin and aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) inhibited IL-4-evoked activation of signal transducer and activator of transcription (STAT) 3, while leaving activation of STAT6 and induction of typical IL-4-responsive genes intact. However, phenformin prevented IL-4-induced association of STAT6 and histone H3K9-acetylation at the ALOX15 promoter. Activating AMPK abolished cellular production of 15-lipoxygenase arachidonic acid metabolites in IL-4-stimulated macrophages, which was mimicked by an ALOX15 knockdown. Finally, pre-treatment of macrophages with IL-4 for 48h increased the mRNA expression of pro-inflammatory cytokines IL-6, IL-12, CXCL9, CXCL10 induced by subsequent stimulation with lipopolysaccharide. This response was attenuated by inhibition of ALOX15 or activation of AMPK during incubations with IL-4. In conclusion, limiting ALOX15 expression by AMPK may promote an anti-inflammatory phenotype of IL-4-stimulated human macrophages. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Full-text · Article · Aug 2015 · Journal of Biological Chemistry

  • No preview · Article · Aug 2015 · Infection
  • Dominik C. Fuhrmann · Nathalie Dehne · Bernhard Bruene

    No preview · Article · Aug 2015 · American Journal of Hematology
  • Nathalie Dehne · Bernhard Bruene

    No preview · Article · Aug 2015 · American Journal of Hematology
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    Wei Cui · Jie Zhou · Nathalie Dehne · Bernhard Brüne
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    ABSTRACT: Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined. Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2. Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.
    Full-text · Article · Jul 2015 · Cell and Bioscience
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    ABSTRACT: AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor δ (PPARδ) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.
    Full-text · Article · Jun 2015 · PLoS ONE

  • No preview · Article · Jun 2015 · Circulation
  • Marcel Boß · Marina Kemmerer · Bernhard Brüne · Dmitry Namgaladze
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    ABSTRACT: Macrophages, converted to lipid-loaded foam cells, accumulate in atherosclerotic lesions. Macrophage lipid metabolism is transcriptionally regulated by peroxisome proliferator-activated receptor gamma (PPARγ), and its target gene fatty acid binding protein 4 (FABP4) accelerates the progression of atherosclerosis in mouse models. Since expression of PPARγ and FABP4 is increased upon interleukin-4 (IL-4)-induced macrophage polarization, we aimed to investigate the role of FABP4 in human IL-4-polarized macrophages. We investigated the impact of FABP4 on PPARγ-dependent gene expression in primary human monocytes differentiated to macrophages in the presence of IL-4. IL-4 increased PPARγ and its target genes lipoprotein lipase (LPL) and FABP4 compared to non-polarized or LPS/interferon γ-stimulated macrophages. LPL expression correlated with increased very low density lipoprotein (VLDL)-induced triglyceride accumulation in IL-4-polarized macrophages, which was sensitive to inhibition of lipolysis or PPARγ antagonism. Inhibition of FABP4 during differentiation using chemical inhibitors BMS309403 and HTS01037 or FABP4 siRNA decreased the expression of FABP4 and LPL, and reduced lipid accumulation in macrophages treated with VLDL. FABP4 or LPL inhibition also reduced the expression of inflammatory mediators chemokine (C-C motif) ligand 2 (CCL2) and IL-1β in response to VLDL in IL-4-polarized macrophages. PPARγ luciferase reporter assays confirmed that FABP4 supports fatty acid-induced PPARγ activation. Our findings suggest that IL-4 induces a lipid-accumulating macrophage phenotype by activating PPARγ and subsequent LPL expression. Inhibition of FABP4 decreases VLDL-induced foam cell formation, indicating that anti-atherosclerotic effects achieved by FABP4 inhibition in mouse models may be feasible in the human system as well. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Apr 2015 · Atherosclerosis
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    ABSTRACT: Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1-/- PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1-/- macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.
    Full-text · Article · Mar 2015 · Oncotarget
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    ABSTRACT: Tumor-associated lymphangiogenesis was identified as an important clinical determinant for the prognosis of HCC and significantly influences patient survival. However, in this context little is known about regulation of lymphangiogenesis by hypoxia inducible factors. In HCC mainly HIF-1α was positively correlated with lymphatic invasion and metastasis, while a defined role of HIF-2α is missing. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies. This constitutes an in vitro tumor model mimicking the cancer microenvironment and allows addressing the role of distinct HIF isoforms in regulating HCC lymphangiogenesis. In cocultures with a HIF-2α knockdown lymphangiogenesis was significantly increased, while the knockdown of HIF-1α showed no effect. The HIF-2α-dependent lymphangiogenic phenotype was confirmed in vivo using matrigel plug assays with supernatants of HIF-2α knockdown HepG2 cells. We identified and verified IGFBP1 as a HIF-2α target gene. The potential of HepG2 cells to induce lymphangiogenesis in two independent functional assays was significantly enhanced either by a knockdown of HIF-2α or by silencing IGFBP1. Moreover, we confirmed IGF as a potent pro-lymphatic growth factor with IGFBP1 being its negative modulator. We propose that HIF-2α acts as an important negative regulator of hepatic lymphangiogenesis in vitro and in vivo by inducing IGFBP1 and thus, interfering with IGF-signaling. Therefore, HIF-2α may constitute a critical target in HCC therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2015 · Biology of the Cell

  • No preview · Article · Mar 2015 · Endoskopie heute
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    ABSTRACT: Understanding of the physiological role of peroxisome proliferator-activated receptor gamma (PPARγ) offers new opportunities for the treatment of cancers, immune disorders and inflammatory diseases. In contrast to PPARγ agonists, few PPARγ antagonists have been studied, though they do exert immunomodulatory effects. Currently, no therapeutically useful PPARγ antagonist is commercially available. The aim of this study was to identify and kinetically characterise a new competitive PPARγ antagonist for therapeutic use. A PPARγ-dependent transactivation assay was used to kinetically characterise (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB) in kidney, T and monocytic cell lines. Cytotoxic effects were analysed and intracellular accumulation of MTTB was assessed by tandem mass spectrometry (LC-MS/MS). Potential interactions of MTTB with the PPARγ protein were suggested by molecular docking analysis. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), MTTB exhibited competitive antagonism against rosiglitazone in HEK293T and Jurkat T cells, with IC50 values in HEK293T cells of 4.3µM and 1.6µM, using the PPARγ ligand binding domain (PPARγ-LBD) and the full PPARγ protein, respectively. In all cell lines used, however, MTTB showed much higher intracellular accumulation than GW9662. MTTB alone exhibited weak partial agonistic effects and low cytotoxicity. Molecular docking of MTTB with the PPARγ-LBD supported direct interaction with the nuclear receptor. MTTB is a promising prototype for a new class of competitive PPARγ antagonists. It has weak partial agonistic and clear competitive antagonistic characteristics associated with rapid cellular uptake. Compared to commercially available PPARγ modulators, this offers the possibility of dose regulation of PPARγ and immune responses. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Mar 2015 · European Journal of Pharmacology
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    Full-text · Dataset · Feb 2015
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    ABSTRACT: NF-E2-related factor 2 (Nrf2), known to protect against reactive oxygen species (ROS), recently emerged to resolve acute inflammatory responses in activated macrophages. Consequently, disruption of Nrf2 promotes a pro-inflammatory macrophage phenotype. In the current study, we addressed the impact of this macrophage phenotype on CD8+ T cell activation by using an antigen-driven co-culture model consistent of Nrf2-/- and Nrf2+/+ bone marrow derived macrophages (BMDMΦ) and transgenic OT-1 CD8+ T cells. OT-1 CD8+ T cells encode a T cell receptor that specifically recognizes MHCI-presented OVA(257-264) peptide, thereby causing a downstream T cell activation. Interestingly, co-culture of OVA(257-264)-pulsed Nrf2-/- BMDMΦ with transgenic OT-1 CD8+ T cells attenuated CD8+ T cell activation, proliferation, and cytotoxic function, compared to Nrf2+/+ BMDMΦ.Since the provision of low molecular thiols such as glutathione (GSH) or cysteine (Cys) by macrophages limits antigen-driven CD8+ T cell activation, we quantified the amount of intracellular and extracellular GSH and Cys in both co-cultures. Indeed, GSH levels were strongly decreased in Nrf2-/- co-cultures compared to wildtype counterparts. Supplementation of thiols in Nrf2-/- co-cultures via addition of glutathione ester, N-acetylcysteine, β-mercaptoethanol, or cysteine itself restored T cell proliferation as well as cytotoxicity by increasing intracellular GSH. Mechanistically, we identified two potential Nrf2-regulated genes involved in thiol synthesis in BMDMΦ: the cystine transporter subunit xCT and the modulatory subunit of the GSH synthesizing enzyme γ-GCS (GCLM). Pharmacological inhibition of γ-GCS-dependent GSH synthesis as well as knockdown of the cystine importer xCT in Nrf2+/+ BMDMΦ mimicked the effect of Nrf2-/- BMDMΦ on CD8+ T cell function. Our findings demonstrate, that reduced levels of GCLM as well as xCT in Nrf2-/- BMDMΦ limit GSH availability, thereby inhibiting antigen-induced CD8+ T cell function.
    Full-text · Article · Feb 2015 · Free Radical Biology and Medicine
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    ABSTRACT: Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP. Copyright © 2015 by The American Association of Immunologists, Inc.
    No preview · Article · Feb 2015 · The Journal of Immunology
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    ABSTRACT: Abstract The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1-5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient versus wildtype mice. This effect was not due to altered migration of mature pDC, but rather due to a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. Since S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity.
    No preview · Article · Jan 2015 · Biological Chemistry

Publication Stats

13k Citations
1,338.62 Total Impact Points


  • 2005-2015
    • Goethe-Universität Frankfurt am Main
      • • Institute of Biochemistry
      • • Institut für Biochemie I - Pathobiochemie
      Frankfurt, Hesse, Germany
  • 2006-2009
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2002-2005
    • Technische Universität Kaiserslautern
      • Division of Cell Biology
      Kaiserlautern, Rheinland-Pfalz, Germany
  • 2003
    • Universität zu Lübeck
      • Institut für Physiologie
      Lübeck, Schleswig-Holstein, Germany
  • 1995-2002
    • Friedrich-Alexander-University of Erlangen-Nürnberg
      • • Department of Paediatrics
      • • Faculty of Medicine
      Erlangen, Bavaria, Germany
  • 2000-2001
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 1989-1996
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany