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Expression von Selenoproteinen in Monozyten und Makrophagen — Implikationen für das Immunsystem

Expression of selenoproteins in monocytes and macrophages — Implications for the immune system

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Zusammenfassung

□ Monozyten differenzieren unter dem Einfluß von 1,25(OH)2 Vitamin D3 und anderen Faktoren aus myeloischen Vorläuferzellen. Koloniestimulierende Faktoren wie (Granulozyten-)Makrophagen-stimulierender Faktor (GMCSF und MCSF) propagieren die weitere Differenzierung zu Makrophagen. Die Aktivierung von Makrophagen und die Phagozytose von fremden Partikeln sind regelmä\ig begleitet von einem sogenannten „respiratory burst“, einer erhöhten Produktion von reaktiven Sauerstoffspezies (ROS), die durch den Enzymkomplex NADPH-Oxidase bewerkstelligt wird. Gleichzeitig wird eine Anzahl antioxidativer Enzyme exprimiert, um die Zelle vor den zytotoxischen Effekten der ROS zu schützen, die gegen die eingeschlossenen Mikroorganismen gerichtet sind und möglicherweise auch Genregulationen bewirken. Gut charakterisierte Selenoproteine, die in die antioxidative „Defense“-Reaktion der Zelle involviert sind, sind die selenabhängigen Glutathionperoxidasen (zytosolische [cGPx] und plasmatische [pGPx]) und die Thioredoxinreduktasen α und β (TrxRα/β). Das zytosolische Isoenzym der GPx (cGPx) und die TrxRα werden beide im Rahmen der Differenzierung durch 1,25 (OH)2 Vitamin D3 stimuliert. GPx-Isoenzyme neutralisieren H2O2. TrxR sind entweder direkt oder indirekt über ihren Kofaktor Thioredoxin in die Proteinfaltung involviert. Sie reduzieren Sulfhydrylgruppen und beeinflussen so zum Beispiel kritische Protein/Protein-Interaktionen und Protein/DNA-Interktionen; sie modulieren somit die Dimerisation und/oder die DNA-Bindung von Transkriptionsfaktoren (Glukokortikoidrezeptor und andere Steroidhormonrezeptoren, NFκB). Darüber hinaus wurde gezeigt, daß das antibiotische und zytotoxische Peptid NK-Lysin ein Substrat für die TrxRα ist (mit der Folge der Inaktivierung des Peptids), was nahelegt, daß TrxR ein protektiver Faktor für die Zelle selbst ist. Selen wird kontrolliert und spezifisch in Selenoproteine in Form von Selenozystein (Secys) eingebaut, welches in Anwesenheit einer dredimensionalen Haarnadelstruktur der 3′UTR (Secis-Element) am Codon UGA abgelesen wird, das ohne ein geeignetes Secis-Element und im Selenmangel als opales Stop-Codon fungiert. Die oben diskutierten Prozesse können also im Selenmangel alteriert sein und andererseits durch Selensupplementation moduliert werden.

□ Wir haben die TrxRα als 1,25(OH)2 Vitamin D3-responsives Protein in Monozyten charakterisiert und gezeigt, daß die Aktivität der GPx und der TrxR durch Selensupplementation in vitro und ex vivo stimuliert wird. Neuere Arbeiten zeigen, daß Thioredoxin, ein wichtiges Substrat der TrxR, nach Behandlung von Zellen mit H2O2 schnell in den Zellkern wandert. Darüber hinaus ist aber wenig bekannt über die Kompartimentalisierung des „respiratory burst“ in der Zelle und die intrazelluläre Lokalisation der antioxidativen Enzyme während dieses Vorgangs. Die Makrophagenfunktion ist alteriert, wenn der „respiratory burst“ insuffizient ist, wie zum Beispiel bei der hereditären chronischen granulomatösen Erkrankung. Andererseits ist diese aber auch gestört, wenn ein Defizit an antioxidativen Enzymen besteht. Thioredoxin wurde als Wachstumsfaktor für Lymphozyten identifiziert und ist in den „Crosstalk“ zwischen Makrophagen und Lymphozyten involviert. Die Relevanz der beschriebenen und anderer noch nicht charakterisierter Selenoproteine von Monozyten bleibt näher zu charakterisieren, wie auch die der Supplementation von Selen generell in der Nahrungskette und speziell in Situationen von kritischen Infektionen und bei der Entwicklung der Autoimmunität.

Abstract

□ Monocytes differentiate from myeloid precursors towards the macrophage state of differentiation under the influence of 1,25-dihydroxy vitamin D3 (1,25 [OH]2 vitamin D3) and other factors and this is further propagated by colony stimulating factors (MCSF and GMCSF). Macrophage activation and phagocytosis of foreign particles are regularly accompanied by a so called “respiratory burst”, an increase in the production of reactive oxygen species (ROS), exerted by the enzyme complex NADPH oxidase. A number of antioxidant enzymes is expressed at the same time to protect the cells from the cytotoxic effects of ROS directed against engulfed microorganisms. The selenium-dependent glutathione peroxidases and thioredoxin reductases are important examples. The cytosolic GPx isoenzyme (cGPx) and thioredoxin reductase α (TrxRα) are upregulated during the process of differentiation and under the influence of 1,25 (OH)2 vitamin D3. GPx isoenzymes neutralize H2O2. TrxR reduce sulfhydryl-groups like in cysteins either directly or via their cofactor thioredoxin and thus are involved in protein folding and critical protein-protein and protein-DNA interactions, e. g. modulation of dimerization and/or DNA-binding and ligand binding of transcription factors (glucocorticoid receptor and other steroid receptors, NFκB). In addition, the antibiotic peptide NK-lysin was shown to be a substrate for TrxRα, suggesting that TrxR protects the cell itself from the cytotoxic effects of NK-lysin. Selenium is incorporated into selenocysteine (Secys) in a regulated fashion in the presence of a hairpin structure (Secis element) in the 3′UTR of selenoprotein genes. Secis elements direct the insertion of Secys at UGA codons, which function as opal stop codons in the absence of a suitable Secis element and in selenium deficiency. The above mentioned processes might therefore be altered in relative selenium deficiency or vice versa be upregulated through selenium supplementation.

□ We have shown that TrxRα is a 1,25 (OH)2 vitamin D3-responsive early gene in monocytic cells and that TrxR activity as well as GPx activity in these cells can be upregulated by the addition of selenium in vitro and ex vivo. Recent work demonstrates that thioredoxin rapidly enters the cell nucleus upon treatment of cells with H2O2, but little is known about the compartimentalization of the respiratory burst and the intracellular localization of antioxidant enzymes during that process. Macrophage function is insufficient if the generation of a respiratory burst is altered like in hereditary chronic granulomatous disease on one hand, but on the other hand is as well disturbed, if there is a lack in antioxidant enzyme activity. Thioredoxin has been identified as a lymphocyte growth factor and might therefore be involved in the crosstalk between macrophages and lymphocytes. The relevance of the above mentioned and other yet undefined monocytic selenoproteins remains to be elucidated in detail as well as the relevance of selenium supplementation in nutrition in general and in situations of critical infectious disease and autoimmunity.

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  1. Interdisziplinäres Zentrum für Klinische Forschung der Universität Würzburg, Germany

    Regina Ebert-Dümig, Jochen Seufert, Doris Schneider, Josef Köhrle & Franz Jakob

  2. Abteilung für Molekulare Innere Medizin und Klinische Forschergruppe der Medizinischen Poliklinik, Universität Würzburg, Germany

    Jochen Seufert, Josef Köhrle, Norbert Schütze & Franz Jakob

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  1. Regina Ebert-Dümig
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Ebert-Dümig, R., Seufert, J., Schneider, D. et al. Expression von Selenoproteinen in Monozyten und Makrophagen — Implikationen für das Immunsystem. Med Klin 94 (Suppl 3), 29–34 (1999). https://doi.org/10.1007/BF03042187

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