title: Amyloid-β increases metallo- and cysteine protease activities in human macrophages.
abstract: OBJECTIVE
  Amyloid-β (Aβ) plays a crucial role in the onset and progression of atherosclerosis. Macrophages are a source of matrix metalloproteinases (MMPs), cysteine proteases and transforming growth factor (TGF)-β1 in the vascular wall. The aims of this study were to analyze the capacity of Aβ peptide (1-40) (Aβ40), Aβ peptide (1-42) (Aβ42) and fibrillar Aβ42 (fAβ42) to modulate the expression and activity of MMP-9, MMP-2 and tissue inhibitor of MMP-1 (TIMP-1) in human monocyte-derived macrophages (HMDM). Additionally, we analyzed whether Aβ internalization alters the secretion of cathepsin S (CatS) and TGF-β1 by macrophages.
  
  
  METHODS
  HMDM were exposed to native and fibrillar Aβ. MMPs and TIMP-1 expression was analyzed by real-time PCR, and MMP abundance by zymography. Protein levels of precursor and active forms of CatS were analyzed by Western blot and TGF-β1 levels by ELISA.
  
  
  RESULTS
  Aβ40, Aβ42 and especially fAβ42 strongly induced MMP-9/MMP-2 levels. Moreover, we showed enhanced active CatS and reduced TGF-β1 protein levels in the secretome of Aβ42 and fAβ42-exposed macrophages.
  
  
  CONCLUSIONS
  Aβ can regulate the proinflammatory state of human macrophages by inducing metallo- and cysteine protease levels and by reducing TGF-β1 secretion. These effects may be crucial in atherosclerosis progression.
authors: Cardiovascular Research Center CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: José
authors: J
authors: Castellano
authors: Lina
authors: L
authors: Badimon
authors: Vicenta
authors: V
authors: Llorente-Cortés
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008264:Macrophages / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002403:Cathepsins; C028217:cathepsin S; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9