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Department of Surgery, University of Minnesota, Minneapolis, MN 55455
Evidence is provided that macrophages can make M-1 or M-2
responses. The concept of M-1/M-2 fomented from observations that
macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more
easily activated to produce NO with either IFN-
or LPS than
macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS
stimulates Th2, but not Th1, macrophages to increase arginine
metabolism to ornithine. Thus, M-1/M-2 does not simply describe
activated or unactivated macrophages, but cells expressing distinct
metabolic programs. Because NO inhibits cell division, while ornithine
can stimulate cell division (via polyamines), these results also
indicate that M-1 and M-2 responses can influence inflammatory
reactions in opposite ways. Macrophage TGF-ß1, which inhibits
inducible NO synthase and stimulates arginase, appears to play an
important role in regulating the balance between M-1 and M-2. M-1/M-2
phenotypes are independent of T or B lymphocytes because C57BL/6 and
BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2
proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID
macrophages cause CB6F1 lymphocytes to increase
IFN- production, while BALB/c SCID macrophages increase TGF-ß
production. Together, the results indicate that M-1- or M-2-dominant
macrophage responses can influence whether Th1/Th2 or other types of
inflammatory responses occur.
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 J. Yamada, K. Maruyama, Y. Sano, S. Kinoshita, Y. Murata, and J. Hamuro Promotion of Corneal Allograft Survival by the Induction of Oxidative Macrophages Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 448 - 454. [Abstract] [Full Text] [PDF]
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T. Katakura, M. Miyazaki, M. Kobayashi, D. N. Herndon, and F. Suzuki CCL17 and IL-10 as Effectors That Enable Alternatively Activated Macrophages to Inhibit the Generation of Classically Activated Macrophages J. Immunol., February 1, 2004; 172(3): 1407 - 1413. [Abstract] [Full Text] [PDF]
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D. H. Dockrell, H. M. Marriott, L. R. Prince, V. C. Ridger, P. G. Ince, P. G. Hellewell, and M. K. B. Whyte Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection J. Immunol., November 15, 2003; 171(10): 5380 - 5388. [Abstract] [Full Text] [PDF]
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H. Wang, K. A. Hosiawa, W. Min, J. Yang, X. Zhang, B. Garcia, T. E. Ichim, D. Zhou, D. Lian, D. J. Kelvin, et al. Cytokines Regulate the Pattern of Rejection and Susceptibility to Cyclosporine Therapy in Different Mouse Recipient Strains After Cardiac Allografting J. Immunol., October 1, 2003; 171(7): 3823 - 3836. [Abstract] [Full Text] [PDF]
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A. C. La Flamme, K. Ruddenklau, and B. T. Backstrom Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis Infect. Immun., September 1, 2003; 71(9): 4996 - 5004. [Abstract] [Full Text] [PDF]
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Y. Liu, J. A. Van Ginderachter, L. Brys, P. De Baetselier, G. Raes, and A. B. Geldhof Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells J. Immunol., May 15, 2003; 170(10): 5064 - 5074. [Abstract] [Full Text] [PDF]
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S. A. McClellan, X. Huang, R. P. Barrett, N. van Rooijen, and L. D. Hazlett Macrophages Restrict Pseudomonas aeruginosa Growth, Regulate Polymorphonuclear Neutrophil Influx, and Balance Pro- and Anti-Inflammatory Cytokines in BALB/c Mice J. Immunol., May 15, 2003; 170(10): 5219 - 5227. [Abstract] [Full Text] [PDF]
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D. M. Mosser The many faces of macrophage activation J. Leukoc. Biol., February 1, 2003; 73(2): 209 - 212. [Full Text] [PDF]
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 F L M Ricciardolo Multiple roles of nitric oxide in the airways Thorax, February 1, 2003; 58(2): 175 - 182. [Abstract] [Full Text] [PDF]
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E. Kuroda and U. Yamashita Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice J. Immunol., January 15, 2003; 170(2): 757 - 764. [Abstract] [Full Text] [PDF]
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V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
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A. B. Geldhof, J. A. Van Ginderachter, Y. Liu, W. Noel, G. Raes, and P. De Baetselier Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation Blood, December 1, 2002; 100(12): 4049 - 4058. [Abstract] [Full Text] [PDF]
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W. Noel, G. Hassanzadeh, G. Raes, B. Namangala, I. Daems, L. Brys, F. Brombacher, P. D. Baetselier, and A. Beschin Infection Stage-Dependent Modulation of Macrophage Activation in Trypanosoma congolense-Resistant and -Susceptible Mice Infect. Immun., November 1, 2002; 70(11): 6180 - 6187. [Abstract] [Full Text] [PDF]
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J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; 277(45): 42821 - 42829. [Abstract] [Full Text] [PDF]
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D. A. Hume, I. L. Ross, S. R. Himes, R. T. Sasmono, C. A. Wells, and T. Ravasi The mononuclear phagocyte system revisited J. Leukoc. Biol., October 1, 2002; 72(4): 621 - 627. [Abstract] [Full Text] [PDF]
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E. M. Janssen, M. H. M. Wauben, F. P. Nijkamp, W. van Eden, and A. J. M. van Oosterhout Immunomodulatory Effects of Antigen-Pulsed Macrophages in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 257 - 264. [Abstract] [Full Text] [PDF]
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E. Kuroda, T. Kito, and U. Yamashita Reduced Expression of STAT4 and IFN-{gamma} in Macrophages from BALB/c Mice J. Immunol., June 1, 2002; 168(11): 5477 - 5482. [Abstract] [Full Text] [PDF]
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E. Careau, J. Sirois, and E. Y. Bissonnette Characterization of Lung Hyperresponsiveness, Inflammation, and Alveolar Macrophage Mediator Production in Allergy Resistant and Susceptible Rats Am. J. Respir. Cell Mol. Biol., May 1, 2002; 26(5): 579 - 586. [Abstract] [Full Text] [PDF]
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L. Tuckova, J. Novotna, P. Novak, Z. Flegelova, T. Kveton, L. Jelinkova, Z. Zidek, P. Man, and H. Tlaskalova-Hogenova Activation of macrophages by gliadin fragments: isolation and characterization of active peptide J. Leukoc. Biol., April 1, 2002; 71(4): 625 - 631. [Abstract] [Full Text] [PDF]
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J. Huang, F. J. DeGraves, S. D. Lenz, D. Gao, P. Feng, D. Li, T. Schlapp, and B. Kaltenboeck The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease PNAS, March 19, 2002; 99(6): 3914 - 3919. [Abstract] [Full Text] [PDF]
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K. R. B. Bastos, J. M. Alvarez, C. R. F. Marinho, L. V. Rizzo, and M. R. D'Imperio Lima Macrophages from IL-12p40-deficient mice have a bias toward the M2 activation profile J. Leukoc. Biol., February 1, 2002; 71(2): 271 - 278. [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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S.-H. Su, H.-i. Chen, and C. J. Jen C57BL/6 and BALB/c Bronchoalveolar Macrophages Respond Differently to Exercise J. Immunol., November 1, 2001; 167(9): 5084 - 5091. [Abstract] [Full Text] [PDF]
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F.-D. Shi, M. Flodstrom, S. H. Kim, S. Pakala, M. Cleary, H.-G. Ljunggren, and N. Sarvetnick Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase J. Immunol., September 1, 2001; 167(5): 3000 - 3006. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, A. D. Straw, B. Bauman, and E. J. Pearce CD8- Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development J. Immunol., August 15, 2001; 167(4): 1982 - 1988. [Abstract] [Full Text] [PDF]
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L. C. Gavrilescu and E. Y. Denkers IFN-{{gamma}} Overproduction and High Level Apoptosis Are Associated with High but Not Low Virulence Toxoplasma gondii Infection J. Immunol., July 15, 2001; 167(2): 902 - 909. [Abstract] [Full Text] [PDF]
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J. Hori and J. W. Streilein Dynamics of Donor Cell Persistence and Recipient Cell Replacement in Orthotopic Corneal Allografts in Mice Invest. Ophthalmol. Vis. Sci., July 1, 2001; 42(8): 1820 - 1828. [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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