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

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/EBPβ bind to the STAT6 and C/EBP sites noncooperatively. 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.