title: Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta.
abstract: Arginine metabolism in macrophages during infection and inflammation is complex, owing to differential regulation of inducible nitric oxide synthase (iNOS) and arginases by cytokines and other agents. Changes in levels of Th2 cytokines such as interleukin-4 (IL-4) can play important roles in these conditions via effects on arginine metabolism. IL-4 alters macrophage arginine metabolism by inducing arginase I expression and inhibiting nitric oxide production. To determine the molecular basis for induction of arginase I, the promoter of the murine arginase I gene was cloned and analyzed by transfection in RAW 264.7 macrophage cells. IL-4 induction required a composite response element containing STAT6 and C/EBP sites located 2.86 kb upstream of the transcription start site. Competition experiments showed that STAT6 and C/EBPbeta bind to the STAT6 and C/EBP sites non-cooperatively. Elucidation of the mechanisms involved in regulation of arginase I transcription may provide a basis for developing strategies to modulate arginase expression in Th2 cytokine-predominant diseases.
authors.affiliation: Department of Molecular Genetics and Biochemistry, W1255 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gray
authors.forename: Mirjana
authors.initials: M
authors.lastname: Poljakovic
authors.forename: Diane
authors.initials: D
authors.lastname: Kepka-Lenhart
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015847:Interleukin-4 / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D050800:STAT6 Transcription Factor; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D011993:Recombinant Fusion Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D004247:DNA; D008156:Luciferases; D001119:Arginase