Transglutaminase 2 silencing reduced the beta-amyloid-effects on the activation of human THP-1 cells.
The aberrant expression and activation of transglutaminase 2 (TG2), the ubiquitous enzyme which catalyzes calcium-dependent protein cross-linking reactions, has been reported in many inflammatory diseases. Chronic inflammation, mediated by prolonged activation of brain-resident immunocompetent cells, appears to be involved in the pathogenesis of several age-related diseases, such as Alzheimer's disease. Given that increased TG2 expression has been observed in AD brains, this study was aimed to characterize the role of TG2 in THP-1 monocytes stimulated with amyloid-beta (Aβ). Aβ1-42 treatment dose-dependently increased TG2 expression in THP-1 cells. In particular, a fivefold up-regulation of TG2, compared with control cells, was observed in the presence of 0.5 μM Aβ1-42. At the same concentration, Aβ1-42 was able to promote monocyte maturation as suggested by increased expression of the cell surface antigen CD14 as well as the adhesion-promoting factor fibronectin. The stimulation of THP-1 cells with Aβ1-42 also led to a significant up-regulation of tumor necrosis factor α (TNF-α) and matrix metalloproteinase 9 (MMP-9). Interestingly, THP-1 cell transfection with small interfering RNA directed against TG2 was able to reduce Aβ1-42 increased levels of all the examined markers of monocyte maturation (CD14, fibronectin), and activation (TNF-α, MMP-9). These results indicate that TG2 up-regulation is required for the functional THP-1 monocyte activation induced by Aβ1-42. This work suggests that TG2 inhibition may represent a therapeutic target to ameliorate the inflammation and progression in Alzheimer's disease.
Currò
Monica
M
Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Policlinico Universitario, 98125, Messina, Italy.
Ferlazzo
Nadia
N
Condello
Salvatore
S
Caccamo
Daniela
D
Ientile
Riccardo
R
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins