Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells

Activated murine macrophages metabolize arginine by two alternative pathway s involving the enzymes inducible NO synthase (iNOS) or arginase. The balan ce between the two enzymes is competitively regulated by Th1 and Th2 T help er cells via their secreted cytokines: Th1 cells induce iNOS, whereas Th2 c ells induce arginase, Whereas the role of macrophages expressing iNOS as in flammatory cells is well established, the functional competence of macropha ges expressing arginase remains a matter of speculation. Two isoforms of ma mmalian arginases exist, hepatic arginase I and extrahepatic arginase II. W e investigated the regulation of arginase isoforms in murine bone marrow-de rived macrophages (BMM Phi) in the context of Th1 and Th2 stimulation. Surp risingly, in the presence of either Th2 cytokines or Th2 cells, we observe a specific induction of the hepatic isoform arginase I in BMM Phi. Inductio n of arginase I was shown on the mRNA and protein levels and obeyed the rec ently demonstrated synergism among the Th2 cytokines IL-4 and IL-10. Argina se II was detectable in unstimulated BMM Phi, and was not significantly mod ulated by Th1 or Th2 stimulation. Similar to murine BMM Phi, murine bone ma rrow-derived dendritic cells, as well as a dendritic cell line, up-regulate d arginase I expression and arginase activity upon Th2 stimulation, whereas arginase II was never detected. In addition to revealing the unexpected ex pression of arginase I in the macrophage/monocyte lineage, these results un cover a further intriguing parallelism between iNOS and arginase: both have a constitutive and an inducible isoform, the latter regulated by the Th1/T h2 balance.