NDLI: IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression.

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IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression.

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IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Hildner, M. Zintl, F. Samuelsson, B. Kühn, H. Müller, A. Köhler, A. Spanbroek, R. Habenicht, A. J. Rådmark, O.
Description	Author Affiliation: Spanbroek R ( Center for Vascular Medicine, Friedrich Schiller University Jena, Nordhäuserstrasse 78, 99089 Erfurt, Germany. spanbroek@zmkh.ef.uni-jena.de);
Abstract	Dendritic cell (DC) differentiation from human CD34(+) hematopoietic progenitor cells (HPCs) can be triggered in vitro by a combination of cytokines consisting of stem cell factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha. The immune response regulatory cytokines, IL-4 and IL-13, promote DC maturation from HPCs, induce monocyte-DC transdifferentiation, and selectively up-regulate 15-lipoxygenase 1 (15-LO-1) in blood monocytes. To gain more insight into cytokine-regulated eicosanoid production in DCs we studied the effects of IL-4/IL-13 on LO expression during DC differentiation. In the absence of IL-4, DCs that had been generated from CD34(+) HPCs in response to stem cell factor/granulocyte-macrophage colonystimulating factor/tumor necrosis factor alpha expressed high levels of 5-LO and 5-LO activating protein. However, a small subpopulation of eosinophil peroxidase(+) (EOS-PX) cells significantly expressed 15-LO-1. Addition of IL-4 to differentiating DCs led to a marked and selective down-regulation of 5-LO but not of 5-LO activating protein in DCs and in EOS-PX(+) cells and, when added at the onset of DC differentiation, also prevented 5-LO up-regulation. Similar effects were observed during IL-4- or IL-13-dependent monocyte-DC transdifferentiation. Down-regulation of 5-LO was accompanied by up-regulation of 15-LO-1, yielding 15-LO-1(+) 5-LO-deficient DCs. However, transforming growth factor beta1 counteracted the IL-4-dependent inhibition of 5-LO but only minimally affected 15-LO-1 up-regulation. Thus, transforming growth factor beta1 plus IL-4 yielded large mature DCs that coexpress both LOs. Localization of 5-LO in the nucleus and of 15-LO-1 in the cytosol was maintained at all cytokine combinations in all DC phenotypes and in EOS-PX(+) cells. In the absence of IL-4, major eicosanoids of CD34(+)-derived DCs were 5S-hydroxyeicosatetraenoic acid (5S-HETE) and leukotriene B(4), whereas the major eicosanoids of IL-4-treated DCs were 15S-HETE and 5S-15S-diHETE. These actions of IL-4/IL-13 reveal a paradigm of eicosanoid formation consisting of the inhibition of one and the stimulation of another LO in a single leukocyte lineage.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	9
Volume Number	98
Language	English
Publisher	National Academy of Sciences
Publisher Date	2001-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Arachidonate 15-Lipoxygenase Metabolism Arachidonate 5-Lipoxygenase Dendritic Cells Drug Effects Eicosanoids Biosynthesis Interleukin-4 Pharmacology Antigens, CD34 Genetics Cell Differentiation Cells, Cultured Cytology Enzymology Down-Regulation Enzyme Induction Flow Cytometry Granulocyte-Macrophage Colony-Stimulating Factor Hydroxyeicosatetraenoic Acids Interleukin-13 Microscopy, Confocal Monocytes Stem Cell Factor Stem Cells Transforming Growth Factor Beta Transforming Growth Factor Beta1 Tumor Necrosis Factor-alpha Research Support, Non-U.S. Gov't Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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