Enhancer-mediated control of macrophage-specific arginase I expression.
Arginase I expression in the liver must remain constant throughout life to eliminate excess nitrogen via the urea cycle. In contrast, arginase I expression in macrophages is silent until signals from Th2 cytokines such as IL-4 and IL-13 are received and the mRNA is then induced four to five orders of magnitude. Arginase I is hypothesized to play a regulatory and potentially pathogenic role in diseases such as asthma, parasitic, bacterial, and worm infections by modulating NO levels and promoting fibrosis. We show that Th2-inducible arginase I expression in mouse macrophages is controlled by an enhancer that lies -3 kb from the basal promoter. PU.1, IL-4-induced STAT6, and C/EBPbeta assemble at the enhancer and await the effect of another STAT6-regulated protein(s) that must be synthesized de novo. Identification of a powerful extrahepatic regulatory enhancer for arginase I provides potential to manipulate arginase I activity in immune cells while sparing liver urea cycle function.
Pauleau
Anne-Laure
AL
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Rutschman
Robert
R
Lang
Roland
R
Pernis
Alessandra
A
Watowich
Stephanie S
SS
Murray
Peter J
PJ
D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D004790:Enzyme Induction; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D011401:Promoter Regions, Genetic; D050800:STAT6 Transcription Factor; D018418:Th2 Cells / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors
D016207:Cytokines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D001119:Arginase