The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-beta2Glycoprotein I antibodies.
The anti-phospholipid syndrome (APS) is characterized by thrombosis and the presence of anti-phospholipid antibodies (aPL). Tissue factor (TF), the major initiator of the coagulation system, is induced on monocytes by aPL in vitro, explaining, in part, the pathophysiology in this syndrome. However, little is known regarding the nature of the aPL-induced signal transduction pathways leading to TF expression. In this study, we investigated aPL-inducible genes in PBMC using cDNA array system and real-time PCR. Our results indicated that the mitogen-activated protein kinase (MAPK) pathway was related to TF expression when PBMCs were treated, in the presence of beta(2)Glycoprotein I (beta(2)GPI), with human monoclonal anti-beta(2)GPI antibodies [beta(2)GPI-dependent anti-cardiolipin antibodies (aCL/beta(2)GPI)]. Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated with nuclear factor kappaB (NF-kappaB) activation by monoclonal aCL/beta(2)GPI treatment, and that SB203580, a specific p38 MAPK inhibitor, decreased the aCL/beta(2)GPI-induced TF mRNA expression. The p38 MAPK phosphorylation, NF-kappaB translocation and TF mRNA expression triggered by aCL/beta(2)GPI were abolished in the absence of beta(2)GPI. These results demonstrated that the p38 MAPK signaling pathway plays an important role in aPL-induced TF expression on monocytes and suggest that the p38 MAPK may be a possible therapeutic target to modify a pro-thrombotic state in patients with APS.
Department of Medicine II, Hokkaido University Graduate School of Medicine, N-15 W-7, Kita-ku, Sapporo 060-8648, Japan.
Miyuki
M
Bohgaki
Tatsuya
T
Atsumi
Yumi
Y
Yamashita
Shinsuke
S
Yasuda
Yoshie
Y
Sakai
Akira
A
Furusaki
Toshiyuki
T
Bohgaki
Olga
O
Amengual
Yoshiharu
Y
Amasaki
Takao
T
Koike
D000911:Antibodies, Monoclonal / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D053482:beta 2-Glycoprotein I; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D012333:RNA, Messenger; D053482:beta 2-Glycoprotein I; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases