Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes

Xia, Longfei; Zhou, Hong; Hu, Lichao; Xie, Hong; Wang, Ting; Xu, Ya; Liu, Jingjing; Zhang, Xiaolei; Yan, Jinchuan

doi:10.1160/th12-09-0655

Cited by 27 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another MAPK, JUN1/2, was also activated in this process (Zhou et al, 2012). A major discrepancy between the findings reported by Lopez-Pedrera et al (2006) and our results is that we found NF-jB activity can be regulated by several upstream kinases including p38, JNK and ERK (Xia et al, 2013). In contrast to the above-mentioned researches, Bohgaki et al (2004) showed that neither ERK nor JNK pathway was activated through activation of aPL/b2GPI in monocytes.…”

Section: Open Questionscontrasting

confidence: 99%

“…We further investigated whether nuclear NF-jB and AP-1 were activated through anti-b2GPI/b2GPI complex induced-TF expression and regulated by MAPKs and found that treatment of the cells with anti-b2GPI/b2GPI complex could markedly increase the levels of phosphorylated NF-jB (p-NF-jB p65; RelA) and c-Jun (JUN)/AP-1 (p-c-Jun), as well as TF expression (Xia et al, 2013). Both NF-jB inhibitor, pyrrolidine dithiocarbamate (PDTC), and the AP-1 inhibitor, curcumin, could attenuate TF expression induced by anti-b2GPI/b2GPI or APS-IgG/b2GPI complex.…”

Section: Review ª 2013 John Wiley and Sons Ltdmentioning

confidence: 99%

See 1 more Smart Citation

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

Self Cite

View full text Add to dashboard Cite

SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

show abstract

Section: Open Questionscontrasting

confidence: 99%

Section: Review ª 2013 John Wiley and Sons Ltdmentioning

confidence: 99%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among the important signaling intermediates that play a central role in this process are proximal mediators of innate responses, such as NF-kB [80][81][82], p38-MAP kinase [83,84], ERK [85] and IRAK [55] as well as TRIF, MyD88 and TRAF6 [86]. In addition, the PI3K/Akt pathway seems to play a specific role in platelet activation by aPLA.…”

Section: Internalization and Apla Receptorsmentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

View full text Add to dashboard Cite

The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

show abstract

“…The 'two hit hypothesis' might provide a means to reconcile the controversy on the respective roles of TLR2 and TLR4. In this hypothesis TLR4 is required for inducing TLR2 expression on EC [24], while the constitutive expression of TLR2 in monocytes may lead to TLR4-independent results [20,[24][25][26][27]. Furthermore, the translocation of aPLA into late endosomes might contribute to their pathogenic effects [28][29][30].…”

Section: Introductionmentioning

confidence: 98%

NF‐κB is activated from endosomal compartments in antiphospholipid antibodies‐treated human monocytes

Brandt

Fickentscher

Boehlen

et al. 2014

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

To cite this article: Brandt KJ, Fickentscher C, Boehlen F, Kruithof EKO, de Moerloose P. NF-jB is activated from endosomal compartments in antiphospholipid antibodies-treated human monocytes. J Thromb Haemost 2014; 12: 779-91.See also Groot PG, Urbanus RT. Cellular signaling by antiphospholipid antibodies. This issue, pp 773-5 and Gris JC. The hidden activism of the misnamed. This issue, pp 776-8.Summary. Background: The antiphospholipid antibody syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). We recently demonstrated that Toll-like receptor 2 (TLR2) and CD14 contribute to monocyte activation of aPLA. Objective: To study the mechanisms of cell activation by aPLA, leading to pro-coagulant and pro-inflammatory responses. Methods and Results: For this study, we used purified antibodies from the plasmas of 10 different patients with APS and healthy donors. We demonstrate that aPLA, but not control IgG, co-localizes with TLR2 and TLR1 or TLR6 on human monocytes. Blocking antibodies to TLR2, TLR1 or TLR6, but not to TLR4, decreased TNF and tissue factor (TF) responses to aPLA. Pharmacological and siRNA approaches revealed the importance of the clathrin/dynamin-dependent endocytic pathway in cell activation by aPLA. In addition, soluble aPLA induced NF-jB activation, while bead-immobilized aPLA beads, which cannot be internalized, were unable to activate NF-jB. Internalization of aPLA in monocytes and NF-jB activation were dependent on the presence of CD14. Conclusion: We show that TLR2 and its co-receptors, TLR1 and TLR6, contribute to the pathogenicity of aPLA, that aPLA are internalized via clathrin-and CD14-dependent endocytosis and that endocytosis is required for NF-jB activation. Our results contribute to a better understanding of the APS and provide a possible therapeutic approach.

show abstract

Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes

Cited by 27 publications

References 40 publications

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

Receptors involved in cell activation by antiphospholipid antibodies

NF‐κB is activated from endosomal compartments in antiphospholipid antibodies‐treated human monocytes

Contact Info

Product

Resources

About