Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta

Gene. 2005 Jun 20;353(1):98-106. doi: 10.1016/j.gene.2005.04.004.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arginase / genetics*
  • Base Sequence
  • Binding Sites / genetics
  • Binding, Competitive
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Line
  • DNA / genetics
  • DNA / metabolism
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Enzymologic / drug effects
  • Interleukin-4 / pharmacology*
  • Luciferases / genetics
  • Luciferases / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Response Elements / genetics*
  • STAT6 Transcription Factor
  • Sequence Homology, Nucleic Acid
  • Trans-Activators / metabolism*
  • Transcription, Genetic / drug effects
  • Transfection


  • CCAAT-Enhancer-Binding Protein-beta
  • Recombinant Fusion Proteins
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Trans-Activators
  • Interleukin-4
  • DNA
  • Luciferases
  • Arginase

Associated data

  • GENBANK/AY074884