title: Pro-inflammatory effects of the mushroom Agaricus blazei and its consequences on atherosclerosis development.
abstract: OBJECTIVE
  Extracts of the mushroom Agaricus blazei (A. blazei) have been described as possessing immunomodulatory and potentially cancer-protective activities. However, these effects of A. blazei as a functional food have not been fully investigated in vivo.
  
  
  METHODS
  Using apolipoprotein E-deficient (ApoE(-/-)) mice, an experimental model of atherosclerosis, we evaluated the effects of 6 or 12 weeks of A. blazei supplementation on the activation of immune cells in the spleen and blood and on the development of atherosclerosis.
  
  
  RESULTS
  Food intake, weight gain, blood lipid profile, and glycemia were similar between the groups. To evaluate leukocyte homing and activation, mice were injected with (99m)Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of A. blazei-supplemented animals. Analysis of the spleen showed higher levels of activation of neutrophils, NKT cells, and monocytes as well as increased production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more activated in the supplemented group. Atherosclerotic lesion areas were larger in the aorta of supplemented mice and exhibited increased numbers of macrophages and neutrophils and a thinner fibrous cap. A. blazei-induced transcriptional upregulation of molecules linked to macrophage activation (CD36, TLR4), neutrophil chemotaxy (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) were seen after 12 weeks of supplementation.
  
  
  CONCLUSIONS
  This is the first in vivo study showing that the immunostimulatory effect of A. blazei has proatherogenic repercussions. A. blazei enhances local and systemic inflammation, upregulating pro-inflammatory molecules, and enhancing leukocyte homing to atherosclerosis sites without affecting the lipoprotein profile.
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
authors.forename: Juliana L
authors.initials: JL
authors.lastname: Gonçalves
authors.forename: Eric H
authors.initials: EH
authors.lastname: Roma
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Gomes-Santos
authors.forename: Edenil C
authors.initials: EC
authors.lastname: Aguilar
authors.forename: Daniel
authors.initials: D
authors.lastname: Cisalpino
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Fernandes
authors.forename: Angélica T
authors.initials: AT
authors.lastname: Vieira
authors.forename: Dirce R
authors.initials: DR
authors.lastname: Oliveira
authors.forename: Valbert N
authors.initials: VN
authors.lastname: Cardoso
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Jacqueline I
authors.initials: JI
authors.lastname: Alvarez-Leite
mesh_terms: D000364:Agaricus / Q000737:chemistry*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000276:immunology / Q000503:physiopathology*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D048690:Fruiting Bodies, Fungal / Q000737:chemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D007371:Interferon-gamma / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D007155:Immunologic Factors; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D007371:Interferon-gamma; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
references.citation: Atherosclerosis. 2010 May;210(1):1-13
references.pmid: 19931081
references.citation: Transplantation. 2006 Jan 27;81(2):207-13
references.pmid: 16436964
references.citation: Biotherapy. 1998;11(4):259-65
references.pmid: 9950102
references.citation: Scand J Immunol. 2008 Oct;68(4):363-70
references.pmid: 18782264
references.citation: Clin Immunol. 2010 Jan;134(1):5-24
references.pmid: 19740706
references.citation: Transplantation. 2003 Apr 15;75(7):1072-4
references.pmid: 12698106
references.citation: Curr Atheroscler Rep. 2005 Mar;7(2):127-31
references.pmid: 15727728
references.citation: Mediators Inflamm. 2010;2010:453892
references.pmid: 20182627
references.citation: Eur J Obstet Gynecol Reprod Biol. 2004 Sep 10;116(1):103-5
references.pmid: 15294377
references.citation: Circ Res. 2006 Mar 3;98(4):472-9
references.pmid: 16439692
references.citation: Braz J Med Biol Res. 2006 May;39(5):629-35
references.pmid: 16648901
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Evid Based Complement Alternat Med. 2004 Dec;1(3):259-267
references.pmid: 15841259
references.citation: J Nutr. 2000 Sep;130(9):2151-6
references.pmid: 10958806
references.citation: Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2351-7
references.pmid: 15472130
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):84-9
references.pmid: 17991873
references.citation: Immunology. 2005 Mar;114(3):397-409
references.pmid: 15720441
references.citation: Circ Res. 2002 Aug 23;91(4):281-91
references.pmid: 12193460
references.citation: Atherosclerosis. 1987 Dec;68(3):231-40
references.pmid: 3426656
references.citation: Life Sci. 2004 Apr 23;74(23):2827-37
references.pmid: 15050421
references.citation: J Assoc Off Anal Chem. 1989 Jan-Feb;72(1):62-137
references.pmid: 2715138
references.citation: Cell Struct Funct. 2001 Apr;26(2):103-8
references.pmid: 11482452
references.citation: J Nutr. 1993 Nov;123(11):1939-51
references.pmid: 8229312
references.citation: Nucl Med Commun. 2002 Aug;23(8):715-20
references.pmid: 12124475
references.citation: Int Immunopharmacol. 2005 Sep;5(10):1523-32
references.pmid: 16023604
references.citation: J Exp Med. 2004 Feb 2;199(3):417-22
references.pmid: 14744994
references.citation: Am J Pathol. 2002 May;160(5):1755-65
references.pmid: 12000727
references.citation: Evid Based Complement Alternat Med. 2008 Mar;5(1):3-15
references.pmid: 18317543
references.citation: J Clin Invest. 1997 Jun 1;99(11):2752-61
references.pmid: 9169506
references.citation: Methods Enzymol. 1988;162:327-34
references.pmid: 3226313
references.citation: Appl Microbiol Biotechnol. 2004 May;64(4):537-42
references.pmid: 14593506
references.citation: Clin Nucl Med. 2001 Feb;26(2):99-104
references.pmid: 11201494
references.citation: Microbes Infect. 2008 Mar;10(3):276-84
references.pmid: 18316222
references.citation: Circulation. 2000 May 9;101(18):2149-53
references.pmid: 10801754
references.citation: Anal Biochem. 1993 Jan;208(1):10-5
references.pmid: 8434778
references.citation: Atherosclerosis. 2001 Jan;154(1):71-7
references.pmid: 11137084
references.citation: Am J Pathol. 2009 Dec;175(6):2382-91
references.pmid: 19893035
references.citation: J Microbiol Immunol Infect. 2007 Jun;40(3):201-8
references.pmid: 17639159
references.citation: Atherosclerosis. 1991 Aug;89(2-3):247-54
references.pmid: 1793452
references.citation: Blood. 2002 May 1;99(9):3427-31
references.pmid: 11964313
references.citation: Circulation. 1995 Sep 1;92(5):1355-74
references.pmid: 7648691
references.citation: Int J Gynecol Cancer. 2004 Jul-Aug;14(4):589-94
references.pmid: 15304151
references.citation: Eur J Nucl Med. 1998 Jul;25(7):797-9
references.pmid: 9662604
references.citation: Immunopharmacol Immunotoxicol. 2008;30(4):747-60
references.pmid: 18720167
references.citation: Food Chem Toxicol. 2004 Jun;42(6):909-16
references.pmid: 15110099
references.citation: J Lab Clin Med. 2002 Sep;140(3):176-87
references.pmid: 12271275
references.citation: Biol Pharm Bull. 2004 Mar;27(3):404-6
references.pmid: 14993810