title: Activation of MAPKs in the anti-β2GPI/β2GPI-induced tissue factor expression through TLR4/IRAKs pathway in THP-1 cells.
abstract: Our previous study has demonstrated that the Toll-like receptor 4 (TLR4) signaling pathways contribute to the induction of tissue factor (TF) expression by anti-β(2)-glycoprotein I/β(2)-glycoprotein I (anti-β(2)GPI/β(2)GPI) in human acute monocytic leukemia cell line THP-1. In this study, we focused on the identification of the downstream targets of the TLR4 pathways. When THP-1 cells were treated with anti-β(2)GPI/β(2)GPI complex, enhanced TF expression was observed, along with induced phosphorylation of p38, ERK1/2 and JNK1/2 MAPKs. When the activity of MAPKs was blocked by their corresponding inhibitors (SB203580: p38; U0126: ERK; SP600125: JNK), the expression of TF was reduced significantly. Furthermore, the anti-β(2)GPI/β(2)GPI-induced phosphorylation of p38, ERK1/2 and JNK1/2 was inhibited significantly by TAK-242, a blocker of the signaling transduction mediated by the intracellular domain of TLR4; sc-204013, a specific inhibitor of IRAKs, was also able to partially inhibit the phosphorylation of the MAPKs. Our results demonstrated that MAPKs (p38, ERK1/2 and JNK1/2) were the crucial downstream targets of the anti-β(2)GPI/β(2)GPI-triggered TLR4 signaling pathways in THP-1 cells. This essential role of MAPKs may also promote better understanding of the pathogenesis of antiphospholipid syndrome (APS).
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China. hongzhou@ujs.edu.cn
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Xie
authors.forename: Longfei
authors.initials: L
authors.lastname: Xia
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Yan
mesh_terms: D000936:Antigen-Antibody Complex / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D013449:Sulfonamides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053482:beta 2-Glycoprotein I; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D013925:Thromboplastin; D053592:Interleukin-1 Receptor-Associated Kinases