ALTERNATIVE METABOLIC STATES IN MURINE MACROPHAGES REFLECTED BY THE NITRIC-OXIDE SYNTHASE ARGINASE BALANCE - COMPETITIVE REGULATION BY CD4(-CELLS CORRELATES WITH TH1() T)TH2 PHENOTYPE/

Activated murine macrophages metabolize L-arginine via two main pathwa ys that are catalyzed by the inducible enzymes nitric oxide synthase ( iNOS) and arginase, We have previously shown that CD4(+) T cell-derive d cytokines regulate a competitive balance in the expression of both e nzymes in macrophages; Th1-type cytokines induce iNOS while they inhib it arginase, whereas the reverse is the case for Th2-type cytokines, H ere we addressed the regulation of both metabolic pathways by CD4(+) T cells directly. Macrophages were used as APCs for established Th1 and Th2 T cell clones as well as for in vitro polarized Th1 or Th2 T cell s of transgenic mice bearing an MHC class II-restricted TCR, Both syst ems revealed a similar dichotomy in the macrophages; Th1 T cells led t o an exclusive induction of iNOS, whereas Th2 T cells up-regulated arg inase without inducing iNOS. Arginase levels induced by Th2 T cells fa r exceeded those inducible by individual Th2 cytokines, Similarly, hig h arginase levels could be induced by supernatants of Th2 cells stimul ated in various ways. Ab blocking experiments revealed the critical im portance of IL-4 and IL-10 for arginase up-regulation. Finally, strong synergistic effects between IL-4/IL-13 and IL-10 were observed, suffi cient to account for the extraordinarily high arginase activity induce d by Th2 cells. Our results suggest that the iNOS/arginase balance in macrophages is competitively regulated in the context of Th1- vs Th2-d riven immune reactions, most likely by cytokines without the requireme nt for direct cell interaction.