Macrophages: Master regulators of inflammation and fibrosis

Seminars in Liver Disease

Volumn 30, Issue 3, 2010, Pages 245-257

  Wynn, Thomas A ^a   Barron, Luke ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

arginase; chitinase; collagen; Fibrosis; inflammation; interleukin 1; interleukin 13; interleukin 17; myofibroblasts; Relm alpha; stellate cell; transforming growth factor beta; tumor necrosis factor; wound healing

Indexed keywords

ARGINASE 1; CHEMOKINE; CHEMOKINE RECEPTOR CCR2; CHITINASE; COLONY STIMULATING FACTOR 1; FIZZ1 PROTEIN; IMATINIB; INTERLEUKIN 13; INTERLEUKIN 4; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MANNOSE RECEPTOR; MATRIX METALLOPROTEINASE; MONOCYTE CHEMOTACTIC PROTEIN 1; MONOCYTE CHEMOTACTIC PROTEIN 2; MONOCYTE CHEMOTACTIC PROTEIN 3; OSTEOPONTIN; PLATELET DERIVED GROWTH FACTOR; PROTEIN; RANTES; RELM ALPHA PROTEIN; RESISTIN; TISSUE INHIBITOR OF METALLOPROTEINASE; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG;

CYTOKINE RELEASE; DISEASE COURSE; EXTRACELLULAR MATRIX; FIBROBLAST; FIBROGENESIS; HUMAN; INFLAMMATORY CELL; KUPFFER CELL; LIVER FIBROSIS; MACROPHAGE; MACROPHAGE ACTIVATION; NONHUMAN; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SCHISTOSOMIASIS;

ANIMALS; ARGINASE; CYTOKINES; EXTRACELLULAR MATRIX; HEPATIC STELLATE CELLS; HEPATITIS; HUMANS; INFLAMMATION MEDIATORS; LIVER; LIVER CIRRHOSIS; MACROPHAGE ACTIVATION; MACROPHAGES; PHAGOCYTOSIS; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA1;

EID: 77954961992     PISSN: 02728087     EISSN: 10988971     Source Type: Journal    
DOI: 10.1055/s-0030-1255354     Document Type: Review

References (175)

1. Bataller R, Brenner D A. Liver fibrosis. J Clin Invest 2005 115 209-218
2. Iredale J P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007 117 539-548
3. Friedman S L. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008 134 1655-1669
4. Friedman S L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008 88 125-172
5. Wallace K, Burt A D., Wright M C. Liver fibrosis. Biochem J 2008 411 1-18
6. Luckey S W., Petersen D R. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 2001 71 226-240
7. Ramadori G, Armbrust T. Cytokines in the liver. Eur J Gastroenterol Hepatol 2001 13 777-784
8. Ramm G A., Nair V G., Bridle K R., Shepherd R W., Crawford D H. Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia. Am J Pathol 1998 153 527-535
9. Leicester K L., Olynyk J K., Brunt E M., Britton R S., Bacon B R. CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis. Liver Int 2004 24 446-451
10. Thompson R W., Pesce J T., Ramalingam T et al. Cationic amino acid transporter-2 regulates immunity by modulating arginase activity. PLoS Pathog 2008 4 e1000023
11. Friedman S L., Arthur M J. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989 84 1780-1785
12. Wahl S M., McCartney-Francis N, Allen J B., Dougherty E B., Dougherty S F. Macrophage production of TGF-beta and regulation by TGF-beta. Ann N Y Acad Sci 1990 593 188-196
13. Bonner J C., Osornio-Vargas A R., Badgett A, Brody A R. Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages. Am J Respir Cell Mol Biol 1991 5 539-547
14. Wynn T A. Cellular and molecular mechanisms of fibrosis. J Pathol 2008 214 199-210
15. Gasse P, Mary C, Guenon I et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 2007 117 3786-3799
16. Kaviratne M, Hesse M, Leusink M et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J Immunol 2004 173 4020-4029
17. Olman M A. Beyond TGF-beta: a prostaglandin promotes fibrosis. Nat Med 2009 15 1360-1361
18. Oga T, Matsuoka T, Yao C et al. Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta. Nat Med 2009 15 1426-1430
19. Duffield J S., Forbes S J., Constandinou C M. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005 115 56-65
20. Hotchkiss R S., Strasser A, McDunn J E., Swanson P E. Cell death. N Engl J Med 2009 361 1570-1583
21. Rock K L., Kono H. The inflammatory response to cell death. Annu Rev Pathol 2008 3 99-126
22. Fadok V A., Bratton D L., Konowal A, Freed P W., Westcott J Y., Henson P M. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998 101 890-898
23. Takehara T, Tatsumi T, Suzuki T et al. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology 2004 127 1189-1197
24. Iredale J P., Benyon R C., Pickering J et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998 102 538-549
25. Wynn T A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007 117 524-529
26. Otogawa K, Kinoshita K, Fujii H et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol 2007 170 967-980
27. Shi J, Aisaki K, Ikawa Y, Wake K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 1998 153 515-525
28. Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman S L., Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008 135 660-670
29. Douglass A, Wallace K, Parr R et al. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J Hepatol 2008 49 88-98
30. Atabai K, Jame S, Azhar N et al. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J Clin Invest 2009 119 3713-3722
31. Sanderson N, Factor V, Nagy P et al. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci U S A 1995 92 2572-2576
32. Bissell D M., Wang S S., Jarnagin W R., Roll F J. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 1995 96 447-455
33. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003 200 500-503
34. Karlmark K R., Weiskirchen R, Zimmermann H W. et al. Hepatic recruitment of the inflammatory Gr1+monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009 50 261-274
35. Lin S L., Castao A P., Nowlin B T., Lupher M L. Jr, Duffield J S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 2009 183 6733-6743
36. Gressner A M., Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002 7 d793-d807
37. Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med 2003 198 1179-1188
38. Schmid-Kotsas A, Gross H J., Menke A et al. Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-fibronectin in cultured pancreatic stellate cells. Am J Pathol 1999 155 1749-1758
39. Cameron R G., Blendis L M., Neuman M G. Accumulation of macrophages in primary sclerosing cholangitis. Clin Biochem 2001 34 195-201
40. Xing Z, Tremblay G M., Sime P J., Gauldie J. Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation. Am J Pathol 1997 150 59-66
41. Lee C G., Homer R J., Zhu Z et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 2001 194 809-821
42. Fattouh R, Jordana M. TGF-beta, eosinophils and IL-13 in allergic airway remodeling: a critical appraisal with therapeutic considerations. Inflamm Allergy Drug Targets 2008 7 224-236
43. Fattouh R, Midence N G., Arias K et al. Transforming growth factor-beta regulates house dust mite-induced allergic airway inflammation but not airway remodeling. Am J Respir Crit Care Med 2008 177 593-603
44. Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J. Effects of gadolinium chloride (GdCl(3)) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions. J Comp Pathol 2005 133 92-102
45. Taylor P R., Martinez-Pomares L, Stacey M, Lin H H., Brown G D., Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol 2005 23 901-944
46. Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis 2007 27 339-350
47. Meneghin A, Hogaboam C M. Infectious disease, the innate immune response, and fibrosis. J Clin Invest 2007 117 530-538
48. Seki E, De Minicis S, Osterreicher C H. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007 13 1324-1332
49. Marra F, DeFranco R, Grappone C et al. Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E. J Investig Med 1999 47 66-75
50. Tsuneyama K, Harada K, Yasoshima M et al. Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis. J Pathol 2001 193 102-109
51. Seki E, de Minicis S, Inokuchi S et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 2009 50 185-197
52. Okuma T, Terasaki Y, Kaikita K et al. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases. J Pathol 2004 204 594-604
53. Seki E, De Minicis S, Gwak G Y. et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 2009 119 1858-1870
54. Keane M P., Belperio J A., Moore T A. et al. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis. J Immunol 1999 162 5511-5518
55. Kohan M, Bader R, Puxeddu I, Levi-Schaffer F, Breuer R, Berkman N. Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling. Clin Exp Allergy 2007 37 1444-1454
56. Berman J S., Serlin D, Li X et al. Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. Am J Physiol Lung Cell Mol Physiol 2004 286 L1311-L1318
57. Kawashima R, Mochida S, Matsui A et al. Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas. Biochem Biophys Res Commun 1999 256 527-531
58. Persy V P., Verhulst A, Ysebaert D K., De Greef K E., De Broe M E. Reduced postischemic macrophage infiltration and interstitial fibrosis in osteopontin knockout mice. Kidney Int 2003 63 543-553
59. Sahai A, Malladi P, Melin-Aldana H, Green R M., Whitington P F. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol 2004 287 G264-G273
60. Lorena D, Darby I A., Gadeau A P. et al. Osteopontin expression in normal and fibrotic liver. altered liver healing in osteopontin-deficient mice. J Hepatol 2006 44 383-390
61. Wang Y, Mochida S, Kawashima R et al. Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver. J Gastroenterol 2000 35 696-701
62. Martinet Y, Rom W N., Grotendorst G R., Martin G R., Crystal R G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med 1987 317 202-209
63. Bonner J C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004 15 255-273
64. Yoshiji H, Noguchi R, Kuriyama S et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2005 288 G907-G913
65. Zhang Y, Lee T C., Guillemin B, Yu M C., Rom W N. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 1993 150 4188-4196
66. Kolb M, Margetts P J., Anthony D C., Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 2001 107 1529-1536
67. Wilson M S., Madala S K., Ramalingam T R. et al. Bleomycin and IL-1-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med 2010 207 535-552
68. Tiggelman A M., Boers W, Linthorst C, Sala M, Chamuleau R A. Collagen synthesis by human liver (myo)fibroblasts in culture: evidence for a regulatory role of IL-1 beta, IL-4, TGF beta and IFN gamma. J Hepatol 1995 23 307-317
69. Mancini R, Benedetti A, Jezequel A M. An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver. Virchows Arch 1994 424 25-31
70. Leyland H, Gentry J, Arthur M J., Benyon R C. The plasminogen-activating system in hepatic stellate cells. Hepatology 1996 24 1172-1178
71. Salgado S, Garcia J, Vera J et al. Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy. Mol Ther 2000 2 545-551
72. Henderson N C., Mackinnon A C., Farnworth S L. et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 2008 172 288-298
73. Wynes M W., Riches D W. Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. J Immunol 2003 171 3550-3559
74. Bttner C, Skupin A, Reimann T et al. Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. Am J Respir Cell Mol Biol 1997 17 315-325
75. Hayashi N, Matsui K, Tsutsui H et al. Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2 differentiation of hepatic T cells in response to worm antigens. J Immunol 1999 163 6702-6711
76. Wynn T A. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004 4 583-594
77. Chiaramonte M G., Donaldson D D., Cheever A W., Wynn T A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 1999 104 777-785
78. Oriente A, Fedarko N S., Pacocha S E., Huang S K., Lichtenstein L M., Essayan D M. Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J Pharmacol Exp Ther 2000 292 988-994
79. Murray L A., Argentieri R L., Farrell F X. et al. Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2. Int J Biochem Cell Biol 2008 40 2174-2182
80. Hashimoto S, Gon Y, Takeshita I, Maruoka S, Horie T. IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. J Allergy Clin Immunol 2001 107 1001-1008
81. Wynn T A., Cheever A W., Jankovic D et al. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 1995 376 594-596
82. Shi Z, Wakil A E., Rockey D C. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A 1997 94 10663-10668
83. Chiaramonte M G., Cheever A W., Malley J D., Donaldson D D., Wynn T A. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology 2001 34 273-282
84. Hoffmann K F., Cheever A W., Wynn T A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol 2000 164 6406-6416
85. Pesce J, Kaviratne M, Ramalingam T R. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest 2006 116 2044-2055
86. Reiman R M., Thompson R W., Feng C G. et al. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun 2006 74 1471-1479
87. Weng H L., Liu Y, Chen J L. et al. The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis. Hepatology 2009 50 230-243
88. Hesse M, Cheever A W., Jankovic D, Wynn T A. 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 2000 157 945-955
89. Hesse M, Modolell M, La Flamme A C. et al. 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 2001 167 6533-6544
90. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003 3 23-35
91. Pesce J T., Ramalingam T R., Mentink-Kane M M. et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 2009 5 e1000371
92. Song E, Ouyang N, Hrbelt M, Antus B, Wang M, Exton M S. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol 2000 204 19-28
93. Goerdt S, Orfanos C E. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999 10 137-142
94. Doyle A G., Herbein G, Montaner L J. et al. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-gamma. Eur J Immunol 1994 24 1441-1445
95. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992 176 287-292
96. Gordon S. Macrophages and the immune response In: Paul WE Fundamental Immunology. Philadelphia Lippincott-Raven Publishers 1999 533-544
97. Modolell M, Corraliza I M., Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol 1995 25 1101-1104
98. Schebesch C, Kodelja V, Mller C et al. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro. Immunology 1997 92 478-486
99. MacLeod C L. Regulation of cationic amino acid transporter (CAT) gene expression. Biochem Soc Trans 1996 24 846-852
100. Gangadharan B, Hoeve M A., Allen J E. et al. Murine gammaherpesvirus- induced fibrosis is associated with the development of alternatively activated macrophages. J Leukoc Biol 2008 84 50-58
101. Migliaccio C T., Buford M C., Jessop F, Holian A. The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosis. J Leukoc Biol 2008 83 630-639
102. Prasse A, Pechkovsky D V., Toews G B. et al. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med 2006 173 781-792
103. El Kasmi K C., Qualls J E., Pesce J T. et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 2008 9 1399-1406
104. Frey A B. Myeloid suppressor cells regulate the adaptive immune response to cancer. J Clin Invest 2006 116 2587-2590
105. Loke P, Nair M G., Guiliano D et al. IL-4 dependent alternatively- activated macrophages have a distinctive in vivo gene expression phenotype. Biomed Central 2002 3 7
106. Raes G, Baetselier P D., Noel W et al. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 2002 71 597-602
107. Sandler N G., Mentink-Kane M M., Cheever A W., Wynn T A. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol 2003 171 3655-3667
108. Holcomb I N., Kabakoff R C., Chan B et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000 19 4046-4055
109. Gerstmayer B, Ksters D, Gebel S et al. Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics 2003 81 588-595
110. Betowski J. Adiponectin and resistinnew hormones of white adipose tissue. Med Sci Monit 2003 9 RA55-RA61
111. Liu T, Jin H, Ullenbruch M et al. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol 2004 173 3425-3431
112. Sttz A M., Pickart L A., Trifilieff A, Baumruker T, Prieschl-Strassmayr E, Woisetschlger M. The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol 2003 170 1789-1796
113. Nair M G., Cochrane D W., Allen J E. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett 2003 85 173-180
114. Edwards J P., Zhang X, Frauwirth K A., Mosser D M. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 2006 80 1298-1307
115. Raes G, Nol W, Beschin A, Brys L, de Baetselier P, Hassanzadeh G H. FIZZ1 and Ym as tools to discriminate between differentially activated macrophages. Dev Immunol 2002 9 151-159
116. Liu T, Dhanasekaran S M., Jin H et al. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol 2004 164 1315-1326
117. Liu T, Hu B, Choi Y Y. et al. Notch1 signaling in FIZZ1 induction of myofibroblast differentiation. Am J Pathol 2009 174 1745-1755
118. Chung M J., Liu T, Ullenbruch M, Phan S H. Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts. J Pathol 2007 212 180-187
119. Mishra A, Wang M, Schlotman J et al. Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung. Am J Physiol Lung Cell Mol Physiol 2007 293 L305-L313
120. Anthony R M., Urban J F. Jr, Alem F et al. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med 2006 12 955-960
121. Loke P, Gallagher I, Nair M G. et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 2007 179 3926-3936
122. Reece J J., Siracusa M C., Scott A L. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect Immun 2006 74 4970-4981
123. Anthony R M., Rutitzky L I., Urban J F. Jr, Stadecker M J., Gause W C. Protective immune mechanisms in helminth infection. Nat Rev Immunol 2007 7 975-987
124. Wilson M S., Mentink-Kane M M., Pesce J T., Ramalingam T R., Thompson R, Wynn T A. Immunopathology of schistosomiasis. Immunol Cell Biol 2007 85 148-154
125. Nair M G., Gallagher I J., Taylor M D. et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 2005 73 385-394
126. Pesce J T., Ramalingam T R., Wilson M S. et al. Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog 2009 5 e1000393
127. Nair M G., Du Y, Perrigoue J G. et al. Alternatively activated macrophage-derived RELM-alpha is a negative regulator of type 2 inflammation in the lung. J Exp Med 2009 206 937-952
128. Guan S P., Mok Y K., Koo K N., Chu K L., Wong W S. Chitinases: biomarkers for human diseases. Protein Pept Lett 2009 16 490-498
129. Sutherland T E., Maizels R M., Allen J E. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies. Clin Exp Allergy 2009 39 943-955
130. Reese T A., Liang H E., Tager A M. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 2007 447 92-96
131. Zhu Z, Zheng T, Homer R J. et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 2004 304 1678-1682
132. Lee C G., Hartl D, Lee G R. et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med 2009 206 1149-1166
133. Boot R G., Renkema G H., Strijland A, van Zonneveld A J., Aerts J M. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem 1995 270 26252-26256
134. Malaguarnera L. Chitotriosidase: the yin and yang. Cell Mol Life Sci 2006 63 3018-3029
135. Malaguarnera L, Di Rosa M, Zambito A M., dell'Ombra N, Nicoletti F, Malaguarnera M. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 2006 55 1313-1320
136. Malaguarnera L, Rosa M D., Zambito A M., dell'Ombra N, Marco R D., Malaguarnera M. Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. Am J Gastroenterol 2006 101 2060-2069 (Pubitemid 44337632)
137. Bargagli E, Margollicci M, Luddi A et al. Chitotriosidase activity in patients with interstitial lung diseases. Respir Med 2007 101 2176-2181 (Pubitemid 47324238)
138. Tercelj M, Salobir B, Simcic S, Wraber B, Zupancic M, Rylander R. Chitotriosidase activity in sarcoidosis and some other pulmonary diseases. Scand J Clin Lab Invest 2009 69 575-578
139. Tran A, Benzaken S, Saint-Paul M C. et al. Chondrex (YKL-40), a potential new serum fibrosis marker in patients with alcoholic liver disease. Eur J Gastroenterol Hepatol 2000 12 989-993
140. Johansen J S., Krabbe K S., Mller K, Pedersen B K. Circulating YKL-40 levels during human endotoxaemia. Clin Exp Immunol 2005 140 343-348
141. Junker N, Johansen J S., Andersen C B., Kristjansen P E. Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. Lung Cancer 2005 48 223-231
142. Johansen J S., Milman N, Hansen M, Garbarsch C, Price P A., Graudal N. Increased serum YKL-40 in patients with pulmonary sarcoidosisa potential marker of disease activity? Respir Med 2005 99 396-402
143. Hoffmann K F., McCarty T C., Segal D H. et al. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions. FASEB J 2001 15 2545-2547
144. Troidl C, Mllmann H, Nef H et al. Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction. J Cell Mol Med 2009 13 3485-3496
145. Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol 1998 160 5347-5354
146. Morris S M. Jr, Kepka-Lenhart D, Chen L C. Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells. Am J Physiol 1998 275 (5 Pt 1) E740-E747
147. Dunn M A., Rojkind M, Warren K S., Hait P K., Rifas L, Seifter S. Liver collagen synthesis in murine schistosomiasis. J Clin Invest 1977 59 666-674
148. Shearer J D., Richards J R., Mills C D., Caldwell M D. Differential regulation of macrophage arginine metabolism: a proposed role in wound healing. Am J Physiol 1997 272 (2 Pt 1) E181-E190
149. Endo M, Oyadomari S, Terasaki Y et al. Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung. Am J Physiol Lung Cell Mol Physiol 2003 285 L313-L321
150. Desguerre I, Mayer M, Leturcq F, Barbet J P., Gherardi R K., Christov C. Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation. J Neuropathol Exp Neurol 2009 68 762-773
151. Herbert D R., Hlscher C, Mohrs M et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 2004 20 623-635 (Pubitemid 38659504)
152. Yang M, Rangasamy D, Matthaei K I. et al. Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness. J Immunol 2006 177 5595-5603
153. Zhao A, Urban J F. Jr, Anthony R M. et al. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology 2008 135 217-225
154. Abbas A K., Murphy K M., Sher A. Functional diversity of helper T lymphocytes. Nature 1996 383 787-793
155. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005 5 641-654
156. Gallina G, Dolcetti L, Serafini P et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 2006 116 2777-2790
157. Rodriguez P C., Quiceno D G., Zabaleta J et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 2004 64 5839-5849
158. Mills C D., Kincaid K, Alt J M., Heilman M J., Hill A M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000 164 6166-6173
159. Segawa M, Fukada S, Yamamoto Y et al. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp Cell Res 2008 314 3232-3244
160. Zimmermann N, King N E., Laporte J et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 2003 111 1863-1874
161. Nishida M, Okumura Y, Fujimoto S, Shiraishi I, Itoi T, Hamaoka K. Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem Biophys Res Commun 2005 332 11-16
162. Harty M W., Papa E F., Huddleston H M. et al. Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers. Surgery 2008 143 667-678
163. Mitchell C, Couton D, Couty J P. et al. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol 2009 174 1766-1775
164. Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol 2003 23 103-108
165. Roggin K K., Papa E F., Kurkchubasche A G., Tracy T F. Jr. Kupffer cell inactivation delays repair in a rat model of reversible biliary obstruction. J Surg Res 2000 90 166-173
166. Fallowfield J A., Mizuno M, Kendall T J. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007 178 5288-5295
167. Madala S K., Pesce J T., Ramalingam T R. et al. Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis. J Immunol 2010 184 3955-3963
168. Cabrera S, Gaxiola M, Arreola J L. et al. Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin. Int J Biochem Cell Biol 2007 39 2324-2338
169. Hironaka K, Sakaida I, Matsumura Y, Kaino S, Miyamoto K, Okita K. Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig serum-induced rat liver fibrosis. Biochem Biophys Res Commun 2000 267 290-295
170. Uchinami H, Seki E, Brenner D A., D'Armiento J. Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis. Hepatology 2006 44 420-429
171. Imamura M, Ogawa T, Sasaguri Y, Chayama K, Ueno H. Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats. Gastroenterology 2005 128 138-146
172. Gross T J., Hunninghake G W. Idiopathic pulmonary fibrosis. N Engl J Med 2001 345 517-525
173. Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006 367 241-251
174. Berenguer M, Aguilera V, Prieto M et al. Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. J Hepatol 2006 44 717-722
175. Issa R, Zhou X, Trim N et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J 2003 17 47-49