Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: Granulomatous pathology is shaped by the pattern of L-arginine metabolism

Type 2 cytokines regulate fibrotic liver pathology in mice infected with Sc histosoma mansoni. Switching the immune response to a type 1-dominant react ion has proven highly effective at reducing the pathologic response. Activa tion of NOS-2 is critical, because type 1-deviated/NO synthase 2 (NOS-2) -d eficient mice completely fail to control their response. Here, we demonstra te the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis. Using cytokine-deficient mice and two granuloma models, we show that induction of Arg-1 is type 2 cy tokine dependent. Schistosome eggs induce Arg-1, while Mycobacterium avium- infected mice develop a dominant NOS-2 response. IFN-gamma suppresses Arg-1 activity, because type 1 polarized IL-4/IL-10-deficient, IL-4/IL-13-defici ent, and egg/IL-12-sensitized animals fail to up-regulate Arg-1 following e gg exposure. Notably, granuloma size decreases in these type-1-deviated/Arg -1-unresponsive mice, suggesting an important regulatory role for Arg-1 in schistosome egg-induced pathology. To test this hypothesis, we administered difluoromethylornithine to block ornithine-aminodecarboxylase, which uses the product of arginine metabolism, L-ornithine, to generate polyamines. St rikingly, granuloma size and hepatic fibrosis increased in the ornithine-am inodecarboxylase-inhibited mice. Furthermore, we show that type 2 cytokine- stimulated macrophages produce proline under strict arginase control. Toget her, these data reveal an important regulatory role for the arginase biosyn thetic pathway in the regulation of inflammation and demonstrate that diffe rential activation of Arg-1/NOS-2 is a critical determinant in the pathogen esis of granuloma formation.