Involvement of IRAKs and TRAFs in anti-β2GPI/β2GPI-induced tissue factor expression in THP-1 cells

Guoying Xu; Haiping Wen; Zhou Hong; Donglin Guo; Fang Zhou; Dongdong Chen; Hongxiang Xie; Ting Wang; Haibo Wang

doi:10.1160/TH11-04-0229

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(06): 1158-1169
DOI: 10.1160/TH11-04-0229

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Involvement of IRAKs and TRAFs in anti-β²GPI/β²GPI-induced tissue factor expression in THP-1 cells

Guoying Xu^*

,

Haiping Wen^*

,

Zhou Hong

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Donglin Guo

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Fang Zhou

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Dongdong Chen

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Hongxiang Xie

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Ting Wang

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

,

Haibo Wang

¹Department of Clinical Laboratory and Hematology, Jiangsu University, Zhenjiang, Jiangsu, PR China

› Author Affiliations

Abstract

Summary

Our previous study has shown that Toll-like receptor 4 (TLR4) and its signalling pathway contribute to anti-β²-glycoprotein I/β²-glycoprotein I (anti-β²GPI/β²GPI)-induced tissue factor (TF) expression in human acute monocytic leukaemia cell line THP-1 and annexin A2 (ANX2) is involved in this pathway. However, its downstream molecules have not been well explored. In this study, we have established that interleukin-1 receptor-associated kinases (IRAKs) and tumour necrosis factor receptor-associated factors (TRAFs) are crucial downstream molecules of anti-β²GPI/β²GPI-induced TLR4 signaling pathway in THP-1 cells and explored the potential mechanisms of their self-regulation. Treatment of THP-1 cells with anti-β²GPI/β²GPI complex induced IRAKs and TRAFs expression and activation. Anti-β²GPI/β²GPI complex firstly induced expression of IRAK4 and IRAK1, then IRAK1 phosphorylation and last IRAK3 upregulation. In addition, anti-β²GPI/β²GPI complex simultaneously and acutely enhanced mRNA levels of TRAF6, TRAF4 and zinc finger protein A20 (A20), while chronically increased A20 protein level. Moreover, anti-β²GPI/β²GPI complex-induced IRAKs and TRAFs expression and activation were attenuated by knockdown of ANX2 by infection with ANX2-specific RNA interference lentiviruses (LV-RNAi-ANX2) or by treatment with paclitaxel, which inhibits TLR4 as an antagonist of myeloid differentiation protein 2 (MD-2) ligand. Furthermore, both IRAK1/4 inhibitor and a specific proteasome inhibitor MG-132 could attenuate TRAFs expression as well as TF expression induced by anti-β²GPI/β²GPI complex. In conclusion, our results indicate that IRAKs and TRAFs play important roles in anti-β²GPI/β²GPI-stimulated TLR4/TF signaling pathway in THP-1 cells and contribute to the pathological processes of antiphospholipid syndrome (APS).

Keywords

Anti-β²-glycoprotein I antibodies - β²-glycoprotein I - IRAKs - TRAFs - tissue factor

Full Text

References

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