Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells

Activated macrophages avidly consume arginine via the action of inducible nitric oxide synthase (iNOS) and/or arginase. In contrast to our knowledge regarding macrophage iNOS expression, the stimuli and mechanisms that regulate expression of the cytosolic type I (arginase I) or mitochondrial type II (arginase II) isoforms of arginase in macrophages are poorly defined. We show that one or both arginase isoforms may be induced in the RAW 264.7 murine macrophage cell line and that arginase expression is regulated independently of iNOS expression. For example, 8-bromo-cAMP strongly induced both arginase I and II mRNAs but not iNOS. Whereas interferon-gamma induced iNOS but not arginase, 8-bromo-cAMP and interferon-gamma mutually antagonized induction of iNOS and arginase I mRNAs. Dexamethasone, which did not induce either arginase or iNOS, almost completely abolished induction of arginase I mRNA by 8-bromo-cAMP but enhanced induction of arginase II mRNA. Lipopolysaccharide (LPS) induced arginase II mRNA, but 8-bromo-cAMP plus LPS resulted in synergistic induction of both arginase I and II mRNAs. In all cases, increases in arginase mRNAs were sufficient to account for the increases in arginase activity. These complex patterns of expression suggest that the arginase isoforms may play distinct, although partially overlapping, functional roles in macrophage arginine metabolism.