Bernhard Brüne

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

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Publications (265)1205.55 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: -Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone, 1,25-dihydroxy-vitamin D3 (1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D3 deficiency, however, has been linked to cardiovascular disease as the hormone has anti-inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury.
    Circulation 07/2014; · 15.20 Impact Factor
  • Dmitry Namgaladze, Bernhard Brüne
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    ABSTRACT: Macrophage polarization elicits various metabolic alterations which in turn influence the polarized phenotype. Activation of glycolytic metabolism accompanies and supports macrophage pro-inflammatory M1 polarization. In contrast, M2 polarization of murine macrophages in response to the Th2 cytokine interleukin-4 (IL-4) was linked to the up-regulation of mitochondrial oxidative metabolism and fatty acid oxidation (FAO), which was necessary for coining an IL-4-polarized phenotype. Here we investigated whether similar mechanisms operate in human macrophages stimulated with IL-4. IL-4 causes only moderate changes of mitochondrial oxidative metabolism and FAO, correlating with an unaltered expression of peroxisome proliferator-activated receptor-γ coactivator 1 α/β (PGC-1α/β), the master transcriptional regulators of mitochondrial biogenesis. Furthermore, attenuating FAO had no effect on IL-4-induced polarization-associated gene expression. Apparently, FAO is dispensable for IL-4-induced polarization of human macrophages, pointing to fundamental differences in the metabolic requirements of macrophage phenotype alterations between mice and humans.
    Biochimica et biophysica acta. 06/2014;
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    ABSTRACT: Aim: During sepsis macrophages are alternatively activated towards a M2-like phenotype upon contact with apoptotic cells or their secretion products. Simultaneously NADPH oxidase dependent ROS formation is attenuated, thus contributing to immune paralysis. However the exact mechanism remains elusive. Herein we provide mechanistic insights into diminished mRNA stability of the NADPH oxidase Nox2 upon macrophage M2 polarization and thereby reduced ROS formation in sepsis. Results: Murine J774A.1 macrophages were stimulated with conditioned medium of apoptotic T cells, which reduced Nox2 mRNA and protein expression, consequently decreasing ROS-production. A mRNA pulldown approach coupled to mass spectrometry analysis identified the RNA binding protein SYNCRIP attached to the Nox2 mRNA 3´UTR. The binding of SYNCRIP to the 3´UTR of Nox2 mRNA is attenuated after treatment with conditioned medium of apoptotic T cells, followed by Nox2 mRNA destabilization. In in vivo models of polymicrobial sepsis such as cecal ligation and puncture SYNCRIP was strongly downregulated, which was associated with a decreased Nox2 expression in peritoneal macrophages. Innovation: Downregulation of SYNCRIP in macrophages following contact to material of apoptotic cells destabilized Nox2 mRNA and impaired ROS formation, thereby contributing to a M2 phenotype shift of macrophages in sepsis. Conclusion: M2 polarization of macrophages in sepsis results in an attenuated SYNCRIP binding to the 3'UTR of Nox2 mRNA, destabilizing Nox2 mRNA abundance and expression. Consequently, ROS formation needed to fight against recurrent infections is impaired. In conclusion SYNCRIP regulated Nox2 mRNA degradation mediates the hypoinflammatory phase of sepsis.
    Antioxidants & redox signaling. 05/2014;
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    ABSTRACT: The objective of this study was to investigate, whether the naturally occurring polyphenol resveratrol (Res) enhances the anti-tumor activities of the chemotherapeutic agent oxaliplatin (Ox) in a cell culture model of colorectal cancer, also with regard to a possible inflammatory response and cytotoxic side-effects. Res and Ox in combination synergistically inhibit cell growth of Caco-2 cells, which seems to be due to the induction of different modes of cell death and further leads to an altered cytokine profile of cocultured macrophages. Moreover, combinatorial treatment does not affect non-transformed cells as severe cytotoxicity is not detected in human foreskin fibroblasts and platelets.
    Apoptosis 04/2014; · 4.07 Impact Factor
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    ABSTRACT: Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70kDa ribosomal protein S6 kinase 1 (p70(S6K)) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15 272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70(S6K) cascade. Interference with this pathway occurred downstream of Akt but upstream of p70(S6K). Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC50 of 6.2 μM. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.
    Biochemical pharmacology 02/2014; · 4.25 Impact Factor
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    ABSTRACT: Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA. We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.
    Diabetologia 02/2014; · 6.49 Impact Factor
  • Dmitry Namgaladze, Bernhard Brüne
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    ABSTRACT: Macrophage polarization elicits various metabolic alterations which in turn influence the polarized phenotype. Activation of glycolytic metabolism accompanies and supports macrophage pro-inflammatory M1 polarization. In contrast, M2 polarization of murine macrophages in response to the Th2 cytokine interleukin-4 (IL-4) was linked to the up-regulation of mitochondrial oxidative metabolism and fatty acid oxidation (FAO), which was necessary for coining an IL-4-polarized phenotype. Here we investigated whether similar mechanisms operate in human macrophages stimulated with IL-4. IL-4 causes only moderate changes of mitochondrial oxidative metabolism and FAO, correlating with an unaltered expression of peroxisome proliferator-activated receptor-γ coactivator 1 α/β (PGC-1α/β), the master transcriptional regulators of mitochondrial biogenesis. Furthermore, attenuating FAO had no effect on IL-4-induced polarization-associated gene expression. Apparently, FAO is dispensable for IL-4-induced polarization of human macrophages, pointing to fundamental differences in the metabolic requirements of macrophage phenotype alterations between mice and humans.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 01/2014; · 4.13 Impact Factor
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    ABSTRACT: Rapid alterations in protein expression are commonly regulated by adjusting translation. In addition to cap-dependent translation, which is e.g. induced by pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, alternative modes of translation, such as internal ribosome entry site (IRES)-dependent translation, are often enhanced under stress conditions, even if cap-dependent translation is attenuated. Common stress stimuli comprise nutrient deprivation, hypoxia, but also inflammatory signals supplied by infiltrating immune cells. Yet, the impact of inflammatory microenvironments on translation in tumor cells still remains largely elusive. In the present study, we aimed at identifying translationally deregulated targets in tumor cells under inflammatory conditions. Using polysome profiling and microarray analysis, we identified cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally upregulated in breast tumor cells co-cultured with conditioned medium of activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, we identified and validated an IRES within the 5' untranslated region (5'UTR) of cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, IRES-dependent translation of cyp24a1 by CM was sensitive to phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation of Akt sufficed to induce its IRES activity. Our data provide evidence that cyp24a1 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment. Considering the negative feedback impact of cyp24a1 on the vitamin D responses, the identification of a novel, translational mechanism of cyp24a1 regulation might open new possibilities to overcome the current limitations of vitamin D as tumor therapeutic option.
    PLoS ONE 01/2014; 9(1):e85314. · 3.73 Impact Factor
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    ABSTRACT: miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differentiated with all-trans retinoic acid (ATRA) to promote differentiation, and the effect of let-7 silencing during differentiation was tested. Results indicate that ASCs cultured with ATRA differentiated into cells of the epithelial lineage. We found that ASCs cultured with ATRA or transfected with miRNA let-7e expressed epithelial markers such as cytokeratin-18 and early renal organogenesis markers such as Pax2, Wt1, Wnt4 and megalin. Conversely, the specific knockdown of miRNA let-7e in ASCs significantly decreased the expression of these genes, indicating its vital role during the differentiation process. Using luciferase reporter assays, we also showed that MMP9 is a direct target of miRNA let-7e. Thus, our results suggest that miRNA let-7e acts as a matrix metalloproteinase-9 (MMP9) inhibitor and differentiation inducer in ASCs.
    Cell Death & Disease 01/2014; 5:e1048. · 6.04 Impact Factor
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    ABSTRACT: Lipoxins belong to the family of so-called pro-resolving endogenous lipid mediators which are derived from arachidonic acid and play a key role in the counter-regulation of inflammation. Arachidonic acid is also precursor of multiple pro-inflammatory lipid mediators, such as prostaglandins and leukotrienes, which are simultaneously present in biological compartments. The close structural relationship between several of these lipid mediators and the absence of blank matrix samples enormously complicates the unequivocal identification of these compounds. The determination of lipoxin A4 has been accomplished by chromatographic separation using a C18 reversed phase column and tandem mass spectrometry detection. Samples were liquid-liquid extracted with ethyl acetate before injection. Identification of the analyte was done based on three criteria: retention time, ratio of the m/z transitions and MS/MS spectrum. To avoid false positive results due to endogenous interferences, the extracted samples were re-injected into a chiral Lux Amylose-2 chromatographic column. The authors recommend the use of chiral chromatography in the determination of pro-resolving lipid mediators, together with transition area ratio and fragmentation spectra to improve selectivity for identification and quantitation purposes.
    Talanta 01/2014; 127:82–87. · 3.50 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE2)-synthesized by cyclooxygenase 2 (COX-2)- has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE2 synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE2 synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE2 synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner.
    Biochemical pharmacology 12/2013; · 4.25 Impact Factor
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    ABSTRACT: Prostacyclin is an important mediator of peripheral painsensation. Here, we investigated its potential participation in mediating neuropathic pain and found that prostacyclin receptor (IP)-knockout mice exhibit markedly decreased pain behaviour. Application of an IP-antagonist to the injury site or selective IP-deficiency in myeloid cells mimicked the antinociceptive effect observed in IP-knockout mice. At the site of nerve injury IP was expressed in interleukin (IL) 1beta-containing resident macrophages, which were less frequent in IP knockout mice. Local administration of the IP-agonist cicaprost inhibited macrophage migration in vitro and promoted accumulation of IP- and IL1beta-expressing cells as well as an increase of IL1beta-concentrations at the application site in vivo. Fittingly, the IL1-receptor antagonist anakinra (IL-1ra) decreased neuropathic pain behaviour in wild type, but not in IP-knockout mice. Finally, continuous, but not single administration, of the cyclooxygenase inhibitor meloxicam early after nerve injury decreased pain behaviour and the number of resident macrophages. Thus, early synthesis of prostacyclin at the site of injury causes accumulation of IL1beta-expressing macrophages as a key step for neuropathic pain after traumatic injury.
    Pain 12/2013; · 5.64 Impact Factor
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    ABSTRACT: Aims: The present study assessed the functions of the transcription factor hypoxia inducible factor (HIF) in sensory neurons in models of acute, inflammatory, ischemic and neuropathic pain. The alpha subunit, HIF1α was specifically deleted in neurons of the dorsal root ganglia by mating HIF1α-flfl mice with SNScre mice. Results: SNS-HIF1α-/- mice were more sensitive to noxious heat and cold pain stimulation than HIF1α-flfl control mice. They also showed heightened first-phase nociceptive responses in the formalin and capsaicin tests with increased numbers of cFos positive neurons in the dorsal horn, and intensified hyperalgesia in early phases after paw inflammation and hind limb ischemia/reperfusion. The behavioral cold and heat pain hypersensitivity was explained by increased calcium fluxes upon transient receptor potential channel activation in primary sensory neurons of SNS-HIF1α-/- mice and lowered electrical activation thresholds of sensory fibers. SNS-HIF1α-/- mice however, developed less neuropathic pain after sciatic nerve injury, associated with an abrogation of HIF1-mediated gene upregulation. Innovation: The results suggest that HIF1α is protective in terms of acute heat and cold pain but in case of ongoing activation in injured neurons it may promote the development of neuropathic pain. Conclusion: The duality of HIF1 in pain regulation may impact on the side effects of drugs targeting HIF1, which are being developed e.g. as anticancer agents. Specifically in patients with cancer neuropathy however, temporary HIF1 inhibition might provide a welcome combination of growth and pain reduction.
    Antioxidants & Redox Signaling 10/2013; · 8.20 Impact Factor
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    ABSTRACT: Hypoxia inducible factors (HIFs) are important mediators of the cellular adaptive response during acute hypoxia. The role of HIF-1 and HIF-2 during prolonged periods of hypoxia, i.e. chronic hypoxia is less defined. Therefore, we used human THP-1 macrophages with a knockdown of either HIF-1α, HIF-2α, or both HIFα-subunits, incubated them for several days under hypoxia (1% O2), and analyzed responses to hypoxia using 2D-DIGE coupled to MS/MS-analysis. Chronic hypoxia was defined as a time point when the early but transient accumulation of HIFα-subunits and mRNA expression of classical HIF target genes returned towards basal levels, with a new steady state that was constant from 72h onwards. From roughly 800 spots, that were regulated comparing normoxia to chronic hypoxia, about 100 proteins were unambiguously assigned during MS/MS-analysis. Interestingly, a number of glycolytic genes were up-regulated, while a number of inner mitochondrial membrane proteins were down-regulated independently of HIF-1α or HIF-2α. Chronic hypoxic conditions depleted the mitochondrial mass by autophagy, which occurred independently of HIF proteins. Macrophages tolerate periods of chronic hypoxia very well and adaptive responses occur, at least in part, independently of HIF-1α and/or HIF-2α and comprise mitophagy as a pathway of particular importance.
    Biochimica et Biophysica Acta 10/2013; · 4.66 Impact Factor
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    ABSTRACT: Macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells is a contributing hallmark to immune suppression during the late phase of sepsis. Although the peroxisome proliferator-activated receptor γ (PPARγ) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPARγ. Assuming that a molecule causing PPARγ activation in macrophages originates in the cell membrane of apoptotic cells we analysed lipid rafts from apoptotic, necrotic, and living human Jurkat T cells which showed the presence of 5-lipoxygenase (5-LO) in lipid rafts of apoptotic cells only. Incubating macrophages with lipid rafts of apoptotic, but not necrotic or living cells, induced PPAR responsive element (PPRE)-driven mRuby reporter gene expression in RAW 264.7 macrophages stably transduced with a 4xPPRE containing vector. Experiments with lipid rafts of apoptotic murine EL4 T cells revealed similar results. To verify the involvement of 5-LO in activating PPARγ in macrophages, Jurkat T cells were incubated with the 5-LO inhibitor MK-866 prior to induction of apoptosis, which failed to induce mRuby expression. Similar results were obtained with lipid rafts of apoptotic EL4 T cells preexposed to the 5-LO inhibitors zileuton and CJ-13610. Interestingly, Jurkat T cells overexpressing 5-LO failed to activate PPARγ in macrophages, while their 5-LO overexpressing apoptotic counterparts did. Our results suggest that during apoptosis 5-LO gets associated with lipid rafts and synthesizes ligands that in turn stimulate PPARγ in macrophages.
    Cellular signalling 09/2013; · 4.09 Impact Factor
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    ABSTRACT: MΦ show a highly versatile phenotype depending on the receiving microenvironmental stimuli. MΦ phenotypes are grouped in three subcategories. One is classically activated MΦ (after stimulation with LPS or IFN-γ), and two are alternatively activated forms, known as wound-healing MΦ (induced by IL-4/IL-13) and regulatory MΦ (induced by IL-10/TGF-β). Besides cytokines, hypoxia defines MΦ functions, as shown for classically activated cells. Yet, little is known about the role of hypoxia and HIF-1 and -2 in wound-healing or regulatory MΦ. HIF target genes (such as ADM), analyzed in alternatively activated MΦ from WT and HIF(-/-) mice, were regulated predominantly by HIF-1 and consistently showed reduced hypoxic induction in MΦ stimulated with IL-4. To gain mechanistic insights, we analyzed HIF expression in polarized MΦ. Classically activated MΦ are characterized by the induction of HIF-1α but reduction of HIF-2α mRNA and protein, whereas wound-healing MΦ decreased HIF-1α protein expression without altering mRNA levels. Analysis of protein stability and expression after proteasomal inhibition pointed to translational regulation of HIF-1α in wound-healing MΦ. Following angiogenic-sprouting using embryonic stem cells exposed to supernatants of MΦ incubated with IL-4 under hypoxia, shorter sprouts were revealed compared with supernatants of hypoxic MΦ without IL-4. Conclusively, IL-4 reduces HIF-1α translation and thus, its activity in MΦ and concomitantly, attenuates their ability to promote angiogenesis under hypoxic conditions.
    Journal of leukocyte biology 09/2013; · 4.99 Impact Factor
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    ABSTRACT: The lipid sphingosine-1-phosphate (S1P) is a chemokine for a variety of immune cells including lymphocytes and monocytes. Migration towards S1P is determined by the S1P receptor expression profile, with S1PR1/3 stimulating and S1PR2 attenuating migration. However, the impact and physiological significance of S1P-induced migration of macrophages is largely unclear. We observed that alternative activation of human macrophages, by IL-4 or apoptotic cells (ACs), enhanced S1PR1 expression. Moreover, ACs provoked macrophage migration towards S1P in an S1PR1-dependent manner as confirmed by pharmacological receptor inhibition and S1PR1-deficient murine macrophages. In a mouse model of resolving peritoneal inflammation, F4/80-driven deletion of S1PR1 reduced post-inflammatory macrophage emigration from inflammatory sites. S1PR1 expression on macrophages might therefore be relevant for restoring tissue homeostasis during the resolution of inflammation. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 08/2013; · 4.97 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor (HIF)-1 is the key transcription factor involved in adaptation of mammals to hypoxia and plays, e.g., a crucial role in cancer angiogenesis. Recent evidence suggests a leading role of HIF-1 in various inflammatory and infectious diseases. Here, we describe the role of HIF-1 in S. aureus infections by investigating the HIF-1 dependent host cell response. For this purpose, transcriptional profiling of HIF-1α-deficient HepG2 and control cells both infected with Staphylococcus aureus was performed. Four hours upon infection, expression of 190 genes was influenced of which 24 were regulated via HIF-1. Lysyl oxidase (LOX) was one of the upregulated genes with a potential impact on the course of a S. aureus infection. LOX is an amine oxidase required for biosynthetic cross-linking of extracellular matrix components. LOX was upregulated in vitro in different cell cultures infected with S. aureus and also in vivo in kidney abscesses of intravenously S. aureus-infected mice, and in clinical skin samples from patients suffering from S. aureus-infections. Inhibition of LOX by beta-aminopropionitrile (BAPN) did not affect the bacterial load in kidneys or blood but influenced significantly abscess morphology and collagenization. Our data provide evidence for a crucial role of HIF-1 regulated LOX in abscess formation.
    Infection and immunity 05/2013; · 4.21 Impact Factor
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    ABSTRACT: Cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2 ) supports the growth of a spectrum of cancers. The potential benefit of COX-2-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) for cancer treatment is however limited by their well-known cardiovascular side-effects. Therefore, targeting microsomal PGE synthase 1 (mPGES-1), the downstream enzyme in the COX-2-dependent pathway of PGE2 production might be attractive, although conflicting data regarding a potential tumor-supporting function of mPGES-1 were reported. We determined the impact of mPGES-1 in human DU145 prostate cancer cell growth. Surprisingly, knockdown of mPGES-1 did not alter growth of DU145 monolayer cells, but efficiently inhibited the growth of DU145 multi-cellular tumor spheroids (MCTS). Opposed to MCTS, monolayer cells did not secrete PGE2 due to a lack of COX-2 expression, which was induced during spheroid formation. Pharmacological inhibition of COX-2 and mPGES-1 supported the crucial role of PGE2 for growth of MCTS. The functionality of spheroid-derived PGE2 was demonstrated by its ability to inhibit cytotoxic T cell activation. When investigating mechanisms of spheroid-induced COX-2 induction, we observed that among microenvironmental factors neither glucose deprivation, hypoxia nor tumor cell apoptosis enhanced COX-2 expression. Interestingly, interfering with apoptosis in spheroids triggered a shift towards necrosis, thus augmenting COX-2 expression. We went on to demonstrate that necrotic cells induced COX-2 mRNA expression and PGE2 secretion from live tumor cells. In conclusion, necrosis-dependent COX-2 up-regulation in MCTS promoted PGE2 -dependent tumor growth and inhibited activated cytotoxic T cells. Hence, blocking mPGES-1 as a therapeutic option may be considered for COX-2/mPGES-1-positive solid cancers. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2013; · 6.20 Impact Factor
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    ABSTRACT: AIMS: Transcriptional regulation through peroxisome proliferator-activated receptor γ (PPARγ) is critical for an altered lipid metabolism during monocyte to macrophage differentiation. Here, we investigated how 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMP-dependent protein kinase (AMPK), affects PPARγ during monocyte differentiation. METHODS AND RESULTS: During differentiation of THP-1 monocytic cells or primary human monocytes to macrophages we observed that AICAR inhibited the expression of PPARγ target genes, such as fatty acid binding protein 4 or CD36. This effect was independent of AICAR conversion to AICAR ribotide and AMPK activation. While AICAR increased PPARγ mRNA expression that paralleled differentiation, it inhibited PPARγ protein synthesis without affecting PPARγ protein stability. Monocytes differentiated to macrophages in the presence of AICAR revealed an attenuated uptake of oxidized low density lipoprotein (oxLDL) and reduced oxLDL-triggered c-Jun N-terminal kinase (JNK) activation. JNK and endoplasmic reticulum stress responses to the saturated fatty acid palmitate were attenuated as well, an effect mimicked by the knockdown of PPARγ. Although PPARγ has been reported to support alternative macrophage activation, AICAR did not inhibit interleukin-4-induced gene expression in differentiating monocytes. CONCLUSIONS: Inhibition of PPARγ-dependent gene expression during monocyte differentiation may contribute to an AICAR-elicited macrophage phenotype characterized by reduced inflammatory responses to modified lipoproteins and saturated fatty acids.
    Cardiovascular research 03/2013; · 5.80 Impact Factor

Publication Stats

7k Citations
1,205.55 Total Impact Points

Institutions

  • 2005–2014
    • Goethe-Universität Frankfurt am Main
      • Institute of Biochemistry
      Frankfurt, Hesse, Germany
  • 2005–2013
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2006–2011
    • Università degli Studi di Teramo
      • Faculty of Veterinary Medicine
      Teramo, Abruzzo, Italy
  • 2005–2006
    • Università degli Studi di Urbino "Carlo Bo"
      • Istituto di Farmacologia e Farmacognosia
      Urbino, The Marches, Italy
  • 2001–2005
    • Technische Universität Kaiserslautern
      • Fachgebiet Zellbiologie
      Kaiserslautern, Rhineland-Palatinate, Germany
  • 1995–2005
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Faculty of Medicine
      Erlangen, Bavaria, Germany
  • 2003
    • Universität zu Lübeck
      • Institut für Physiologie
      Lübeck, Schleswig-Holstein, Germany
  • 2002
    • Sapienza University of Rome
      Roma, Latium, Italy
    • Università della Calabria
      • Department of Pharmaco-Biology
      Rende, Calabria, Italy
  • 1999
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 1997
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 1987–1997
    • Universität Konstanz
      Constance, Baden-Württemberg, Germany
  • 1996
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1993
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 1991
    • Karolinska Institutet
      • Institutet för miljömedicin - IMM
      Solna, Stockholm, Sweden