title: Identification of novel markers of alternative activation and potential endogenous PPARγ ligand production mechanisms in human IL-4 stimulated differentiating macrophages.
abstract: We analyzed global gene expression profiles of IL-4 induced alternatively activated as well as IFNγ+TNFα stimulated classically activated human monocyte derived macrophages and identified novel IL-4 regulated alternative activation marker genes including MS4A4A, SLA, CD180, and ENPP2. Transcription factor prediction analysis of IL-4 regulated genes suggested that the regulated genes are involved in a complex regulation of lipid metabolism, defense against cell metabolism derived reactive oxygen species, and basal expression of inflammation linked genes. Both an in silico transcription activation prediction as well as experimental data suggested the presence of alternative macrophage activation specific endogenous PPARγ ligand producing mechanisms. We found the induction of three enzymes whose activity can potentially generate endogenous PPARγ ligands in an IL-4 dependent manner. These are MAOA, ENPP2, and ALOX15 producing 5-methoxy-indole acetate, lysophosphatidic acid (LPA) and 13-hydroxyoctadienoic acid (13-HODE), and/or 15-hydroxyeicosatetraenoic acid (15-HETE), respectively. Our data suggest that global gene expression profiling, combined with computational transcription activity prediction, can lead to identification of transcriptional networks that underpin cellular subtype specification.
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Life Science Building, Egyetem ter 1, Debrecen H-4012, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Czimmerer
authors.forename: Tamas
authors.initials: T
authors.lastname: Varga
authors.forename: Szilard
authors.initials: S
authors.lastname: Poliska
authors.forename: Istvan
authors.initials: I
authors.lastname: Nemet
authors.forename: Attila
authors.initials: A
authors.lastname: Szanto
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology*; D008024:Ligands; D008041:Linoleic Acids / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D001093:Arachidonate 15-Lipoxygenase; D015415:Biomarkers; D006893:Hydroxyeicosatetraenoic Acids; D007371:Interferon-gamma; D015847:Interleukin-4; D008024:Ligands; D008041:Linoleic Acids; D008246:Lysophospholipids; D008565:Membrane Proteins; D008995:Monoamine Oxidase; D047495:PPAR gamma; D010727:Phosphoric Diester Hydrolases; D016392:Proto-Oncogene Proteins pp60(c-src); D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099189:Lysophospholipase D; C092722:CD180 protein, human; C508598:IL4 protein, human; C424714:MS4A4A protein, human; C490635:SLA protein, human; C024348:13-hydroxy-9,11-octadecadienoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C515716:ALOX15 protein, human; C579458:monoamine oxidase A, human; C032881:lysophosphatidic acid