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Berlin Brandenburg

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  • 1
    In: PLoS ONE, 2014, Vol.9(1)
    Description: In Figure 9B, the upper panel showing the phospho-p38 signals, is turned upside down. The correct Figure 9B can be found at the following link: thumbnail Download: * PPT PowerPoint slide * PNG larger image * TIFF original image Figures Citation: Wöbke...
    Keywords: Correction
    ISSN: PLoS ONE
    E-ISSN: 1932-6203
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  • 2
    In: PLoS ONE, 2013, Vol.8(5)
    Description: CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH) 2 D 3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ∼2.3 kb promoter fragments by TGF-β and 1α,25(OH) 2 D 3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3′UTR reporter construct showed that TGF-β and 1α,25(OH) 2 D 3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH) 2 D 3 on mRNA level, although different mechanisms account for the upregulation of each gene.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: The Journal of biological chemistry, 16 April 2010, Vol.285(16), pp.11846-53
    Description: Peroxisome proliferator-activated receptor gamma (PPARgamma) gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer is associated with impaired PPARgamma expression. Considering that regulation of PPARgamma expression during inflammation is largely unknown, we were interested in elucidating underlying mechanisms. To this end, we initiated an inflammatory response by exposing primary human macrophages to lipopolysaccharide (LPS) and observed a rapid decline of PPARgamma1 expression. Because promoter activities were not affected by LPS, we focused on mRNA stability and noticed a decreased mRNA half-life. As RNA stability is often regulated via 3'-untranslated regions (UTRs), we analyzed the impact of the PPARgamma-3'-UTR by reporter assays using specific constructs. LPS significantly reduced luciferase activity of the pGL3-PPARgamma-3'-UTR, suggesting that PPARgamma1 mRNA is destabilized. Deletion or mutation of a potential microRNA-27a/b (miR-27a/b) binding site within the 3'-UTR restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS exposure, partially reversed PPARgamma1 mRNA decay, whereas miR-27b overexpression decreased PPARgamma1 mRNA content. In addition, LPS further reduced this decay. The functional relevance of miR-27b-dependent PPARgamma1 decrease was proven by inhibition or overexpression of miR-27b, which affected LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-6. We provide evidence that LPS-induced miR-27b contributes to destabilization of PPARgamma1 mRNA. Understanding molecular mechanisms decreasing PPARgamma might help to better appreciate inflammatory diseases.
    Keywords: Micrornas -- Genetics ; Ppar Gamma -- Genetics ; RNA, Messenger -- Genetics
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 4
    Language: English
    In: The Journal of biological chemistry, 20 November 2015, Vol.290(47), pp.28446-55
    Description: The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of ∼6 μM, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 μM RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.
    Keywords: Diabetic Nephropathy ; Drug Discovery ; Gene Expression ; Nuclear Factor 2 (Erythroid-Derived 2-Like Factor) (Nfe2l2) (Nrf2) ; Oxidative Stress ; Protein-Protein Interaction ; Signal Transduction ; Intracellular Signaling Peptides and Proteins -- Metabolism ; Nf-E2-Related Factor 2 -- Metabolism ; Pyrrolidines -- Pharmacology ; Signal Transduction -- Drug Effects ; Sulfonamides -- Pharmacology
    E-ISSN: 1083-351X
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  • 5
    Language: English
    In: Blood, 29 April 2010, Vol.115(17), pp.3531-40
    Description: Execution of physiologic cell death known as apoptosis is tightly regulated and transfers immunologically relevant information. This ensures efficient clearance of dying cells and shapes the phenotype of their "captors" toward anti-inflammatory. Here, we identify a mechanism of sphingosine-1-phosphate production by apoptotic cells. During cell death, sphingosine kinase 2 (SphK2) is cleaved at its N-terminus in a caspase-1-dependent manner. Thereupon, a truncated but enzymatically active fragment of SphK2 is released from cells. This step is coupled to phosphatidylserine exposure, which is a hallmark of apoptosis and a crucial signal for phagocyte/apoptotic cell interaction. Our data link signaling events during apoptosis to the extracellular production of a lipid mediator that affects immune cell attraction and activation.
    Keywords: Apoptosis -- Immunology ; Caspase 1 -- Immunology ; Lysophospholipids -- Immunology ; Phosphotransferases (Alcohol Group Acceptor) -- Immunology ; Sphingosine -- Analogs & Derivatives
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 6
    Language: English
    In: BBA - Molecular and Cell Biology of Lipids, 2010, Vol.1801(1), pp.49-57
    Description: Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation. In this study we investigated the impact of the DNA methylation status of the 5-LO promoter on its activity and the role of methyl DNA binding proteins (MBDs) in transcriptional silencing of the 5-LO promoter. Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the gene. In reporter gene assays with methylated 5-LO promoter constructs, the extent of 5-LO promoter methylation inversely correlated with its activity. Furthermore, we found that MBD1 overexpression repressed 5-LO promoter activity when the CpG sites at the Sp1 binding site close to the transcriptional start site (GC4) were methylated. Gel shift data indicate that recruitment of Sp1 to this binding site is prevented by methylation.
    Keywords: 5‑Lipoxygenase ; DNA Methylation ; Mbd ; Knock Down ; Chromatin Immunoprecipitation ; Promoter Regulation ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 1388-1981
    E-ISSN: 1879-2618
    E-ISSN: 00063002
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  • 7
    Language: English
    In: Cardiovascular Research, 06/01/2013, Vol.98(3), pp.479-487
    ISSN: 0008-6363
    Source: Oxford University Press (via CrossRef)
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  • 8
    In: BioInorganic Reaction Mechanisms, 2013, Vol.9(1), pp.15-25
    Description: Macrophages sense exogenous/endogenous danger signals due to their high functional plasticity and adjust their output signals accordingly. These comprise immune responses with the formation of reactive oxygen species, nitric oxide and pro-inflammatory cytokines, with the assumption that reactive species compose a redox signalling network. However, alternatively polarised macrophages suppress toxic radical formation, producing anti-inflammatory signatures associated with tissue repair, immune modulation, and angiogenesis. To change their mediator profile, we describe macrophage subsets and their response to apoptotic cells, focusing on reactive oxygen/nitrogen species and signalling mechanisms, and how apoptotic cells polarise macrophages to adopt an immune-regulatory, pro-angiogenic, and tumour-promoting phenotype.
    Keywords: Angiogenesis ; Arginase ; Cell Death ; Hif ; Macrophage Polarisation ; Nadph Oxidase ; Nitric Oxide ; Sphingosine-1-Phosphate
    ISSN: 2191-2483
    E-ISSN: 2191-2491
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  • 9
    Language: English
    In: European Journal of Pharmacology, 15 May 2015, Vol.755, pp.16-26
    Description: 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 IC values in HEK293T cells of 4.3 µM and 1.6 µM, 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.
    Keywords: Competitive Pparγ Antagonist ; Mttb ; Pparγ ; Pparγ Agonist ; Pparγ Antagonist ; Spparγms ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 10
    Language: English
    In: Antioxidants & redox signaling, 20 August 2013, Vol.19(6), pp.595-637
    Description: Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors.
    Keywords: Macrophage Activation ; Inflammation -- Metabolism ; Macrophages -- Metabolism
    ISSN: 15230864
    E-ISSN: 1557-7716
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