title: Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity.
abstract: Macrophage arginine metabolism via nitric oxide (NO) synthase and arginase pathways reduces and enhances tumor cell proliferation, respectively. Transforming growth factor-beta (TGF-beta) has been shown to down-regulate the NO synthase pathway. The present study describes the effect of TGF-beta on the arginase pathway. TGF-beta up-regulated arginase activity in rat peritoneal macrophages as assessed by measuring the generation of [14C]urea from [14C]-L-arginine in the presence of NG-monomethyl-L-arginine (L-NMMA). The stimulation, which reached fivefold after a 48-h exposure of macrophages to 10 ng/ml TGF-beta, was due to reduction in Km value of arginase. TGF-beta-induced up-regulation of arginase activity led to the release of more polyamines, mainly putrescine. The role of this up-regulation on macrophage cytotoxicity toward L-929 tumor cells was analyzed in coculture experiments. Macrophages blunted DNA synthesis by L-929 cells as assessed by measuring the incorporation of [3H]TdR into the cells and the proportion of cells in the G2 phase. Addition of TGF-beta in the presence of L-NMMA permitted L-929 cells cocultured with macrophages to resume DNA synthesis. The mechanism responsible for this restoration was the up-regulation of arginase activity rather than the down-regulation of NO synthase activity since TGF-beta in the presence of L-NMMA failed to further reduce NO synthase activity whereas it still enhanced arginase activity; synthetic putrescine (1-10 microM) also blunted macrophage cytotoxicity toward L-929 cells. This is the first evidence that TGF-beta up-regulates arginase activity in macrophages and, hence, limits macrophage-dependent cytostasis.
authors.affiliation: INSERM Unit 64, Tenon Hospital, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Boutard
authors.forename: R
authors.initials: R
authors.lastname: Havouis
authors.forename: B
authors.initials: B
authors.lastname: Fouqueray
authors.forename: C
authors.initials: C
authors.lastname: Philippe
authors.forename: J P
authors.initials: JP
authors.lastname: Moulinoux
authors.forename: L
authors.initials: L
authors.lastname: Baud
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019323:omega-N-Methylarginine
chemical_list: D016212:Transforming Growth Factor beta; D019323:omega-N-Methylarginine; D001120:Arginine; D001119:Arginase