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Max Planck Institut für Immunbiologie, Freiburg, Germany
Activated murine macrophages metabolize L-arginine via two main pathways that are catalyzed by the inducible enzymes nitric oxide synthase (iNOS) and arginase. We have previously shown that CD4+ T cell-derived cytokines regulate a competitive balance in the expression of both enzymes in macrophages; Th1-type cytokines induce iNOS while they inhibit arginase, whereas the reverse is the case for Th2-type cytokines. Here 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 cells of transgenic mice bearing an MHC class II-restricted TCR. Both systems revealed a similar dichotomy in the macrophages; Th1 T cells led to an exclusive induction of iNOS, whereas Th2 T cells up-regulated arginase without inducing iNOS. Arginase levels induced by Th2 T cells far exceeded those inducible by individual Th2 cytokines. Similarly, high arginase levels could be induced by supernatants of Th2 cells stimulated in various ways. Ab blocking experiments revealed the critical importance of IL-4 and IL-10 for arginase up-regulation. Finally, strong synergistic effects between IL-4/IL-13 and IL-10 were observed, sufficient to account for the extraordinarily high arginase activity induced by Th2 cells. Our results suggest that the iNOS/arginase balance in macrophages is competitively regulated in the context of Th1- vs Th2-driven immune reactions, most likely by cytokines without the requirement for direct cell interaction.
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Y. Murata, T. Shimamura, and J. Hamuro The polarization of Th1/Th2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production Int. Immunol., February 1, 2002; 14(2): 201 - 212. [Abstract] [Full Text] [PDF]
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T. Ravasi, C. Wells, A. Forest, D. M. Underhill, B. J. Wainwright, A. Aderem, S. Grimmond, and D. A. Hume Generation of Diversity in the Innate Immune System: Macrophage Heterogeneity Arises from Gene-Autonomous Transcriptional Probability of Individual Inducible Genes J. Immunol., January 1, 2002; 168(1): 44 - 50. [Abstract] [Full Text] [PDF]
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M. Hesse, M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, and T. A. Wynn 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 J. Immunol., December 1, 2001; 167(11): 6533 - 6544. [Abstract] [Full Text] [PDF]
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F. H. Falcone, P'n. Loke, X. Zang, A. S. MacDonald, R. M. Maizels, and J. E. Allen A Brugia malayi Homolog of Macrophage Migration Inhibitory Factor Reveals an Important Link Between Macrophages and Eosinophil Recruitment During Nematode Infection J. Immunol., November 1, 2001; 167(9): 5348 - 5354. [Abstract] [Full Text] [PDF]
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V. Iniesta, L. C. Gomez-Nieto, and I. Corraliza The Inhibition of Arginase by N{omega}-Hydroxy-L-Arginine Controls the Growth of Leishmania Inside Macrophages J. Exp. Med., March 19, 2001; 193(6): 777 - 784. [Abstract] [Full Text] [PDF]
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B. Namangala, P. De Baetselier, W. Noël, L. Brys, and A. Beschin Alternative versus classical macrophage activation during experimental African trypanosomosis J. Leukoc. Biol., March 1, 2001; 69(3): 387 - 396. [Abstract] [Full Text]
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R. Rutschman, R. Lang, M. Hesse, J. N. Ihle, T. A. Wynn, and P. J. Murray Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production J. Immunol., February 15, 2001; 166(4): 2173 - 2177. [Abstract] [Full Text] [PDF]
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I. B. Kremer, M. P. Gould, K. D. Cooper, and F. P. Heinzel Pretreatment with Recombinant Flt3 Ligand Partially Protects against Progressive Cutaneous Leishmaniasis in Susceptible BALB/c Mice Infect. Immun., February 1, 2001; 69(2): 673 - 680. [Abstract] [Full Text] [PDF]
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M. Hesse, A. W. Cheever, D. Jankovic, and T. A. Wynn NOS-2 Mediates the Protective Anti-Inflammatory and Antifibrotic Effects of the Th1-Inducing Adjuvant, IL-12, in a Th2 Model of Granulomatous Disease Am. J. Pathol., September 1, 2000; 157(3): 945 - 955. [Abstract] [Full Text] [PDF]
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M. Munder, K. Eichmann, J. M. Moran, F. Centeno, G. Soler, and M. Modolell Th1/Th2-Regulated Expression of Arginase Isoforms in Murine Macrophages and Dendritic Cells J. Immunol., October 1, 1999; 163(7): 3771 - 3777. [Abstract] [Full Text] [PDF]
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P. Bobe, K. Benihoud, D. Grandjon, P. Opolon, L. L. Pritchard, and R. Huchet Nitric Oxide Mediation of Active Immunosuppression Associated With Graft-Versus-Host Reaction Blood, August 1, 1999; 94(3): 1028 - 1037. [Abstract] [Full Text] [PDF]
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J. J. Lasarte, F. J. Corrales, N. Casares, A. Lopez-Diaz de Cerio, C. Qian, X. Xie, F. Borras-Cuesta, and J. Prieto Different Doses of Adenoviral Vector Expressing IL-12 Enhance or Depress the Immune Response to a Coadministered Antigen: the Role of Nitric Oxide J. Immunol., May 1, 1999; 162(9): 5270 - 5277. [Abstract] [Full Text] [PDF]
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 C. A. Louis, V. Mody, W. L. Henry Jr., J. S. Reichner, and J. E. Albina Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1999; 276(1): R237 - R242. [Abstract] [Full Text] [PDF]
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F. Facchetti, W. Vermi, S. Fiorentini, M. Chilosi, A. Caruso, M. Duse, L. D. Notarangelo, and R. Badolato Expression of Inducible Nitric Oxide Synthase in Human Granulomas and Histiocytic Reactions Am. J. Pathol., January 1, 1999; 154(1): 145 - 152. [Abstract] [Full Text] [PDF]
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