title: Transglutaminase 2 is involved in amyloid-beta1-42-induced pro-inflammatory activation via AP1/JNK signalling pathways in THP-1 monocytes.
abstract: Deposition of amyloid-beta (Aβ) peptides has been shown to induce the release of inflammatory factors by activated microglia and brain infiltrating monocytes/macrophages. Interestingly, the enzyme transglutaminase 2 (TG2) has been shown to play a key role in neuroinflammation and regulation of transcription factors involved in immunomodulation. In this study, we aimed to better elucidate the mechanisms underlying TG2 involvement in the pro-inflammatory signaling pathway activated by fibrillar Aβ1-42in THP-1 monocytes. Cell exposure for 24 h to 500 nM Aβ1-42, induced the up-regulation of CD14, CD16, and TG2, suggesting THP-1 cell functional activation. Aβ1-42also increased the production of reactive oxygen species, that was reduced by the pre-incubation with genistein (25 µg/ml), a soy isoflavone with antioxidant properties. Moreover, IL-1β and IL-6 mRNA transcript and protein levels were eightfold increased in Aβ1-42-treated THP-1 monocytes. Interestingly, these effects were significantly reduced by R283 (~45%), a specific inhibitor of TG activity, and genistein (~40%). Aβ1-42induced the activation of p54/p46 JNK, as well as ERK 1/2 at a lower extent. The inactivation of ERK1/2 signalling pathway, but not JNK, by either genistein or U0126, a MEK1/2 inhibitor, was not able to blunt Aβ1-42-induced TG2 up-regulation, that, instead, was significantly reduced by R283. Aβ1-42also induced AP-1 activation that was not significantly affected by genistein or U0126, while was strongly reduced by R283. Our preliminary findings first suggest that TG2 up-regulation is involved in the pro-inflammatory activation of THP-1 monocytes induced by Aβ1-42via AP1/JNK signalling pathways.
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Currò
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gangemi
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giunta
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.|Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ferlazzo
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Navarra
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy. ientile@unime.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ientile
authors.affiliation: Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Caccamo
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000074084:THP-1 Cells; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002070:Butadienes; D004791:Enzyme Inhibitors; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D009570:Nitriles; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D018808:Transcription Factor AP-1; C113580:U 0126; C075222:amyloid beta-protein (1-42); D019833:Genistein; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; D019204:GTP-Binding Proteins
keywords: AP1; Amyloid-beta1–42; Cytokines; R283; THP-1 monocytes; Transglutaminase 2