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

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).

[1]  Pojen P. Chen,et al.  Antiphospholipid Antibodies Affect Human Endometrial Angiogenesis: Protective Effect of a Synthetic Peptide (TIFI) Mimicking the Phospholipid Binding Site of β2glycoprotein I , 2013, American journal of reproductive immunology.

[2]  V. Bogdanov,et al.  Alternatively spliced tissue factor: discovery, insights, clinical implications. , 2011, Frontiers in bioscience.

[3]  H. Zhou,et al.  Toll‐like receptor (TLR)‐4 mediates anti‐β2GPI/β2GPI‐induced tissue factor expression in THP‐1 cells , 2011, Clinical and experimental immunology.

[4]  P. D. de Groot,et al.  Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. , 2010, Blood.

[5]  Y. Shoenfeld,et al.  TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I , 2010, The Journal of Immunology.

[6]  D. Isenberg,et al.  Effects of Polyclonal IgG Derived from Patients with Different Clinical Types of the Antiphospholipid Syndrome on Monocyte Signaling Pathways , 2010, The Journal of Immunology.

[7]  N. Mackman,et al.  Tissue factor and thrombosis: The clot starts here , 2010, Thrombosis and Haemostasis.

[8]  Silvia M Bacot,et al.  Annexin A2 tetramer activates human and murine macrophages through TLR4. , 2010, Blood.

[9]  G. Panayotou,et al.  {beta}2 Glycoprotein I ({beta}2GPI) binds platelet factor 4 (PF4): implications for the pathogenesis of antiphospholipid syndrome. , 2010, Blood.

[10]  K. Hajjar,et al.  Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo. , 2009, Blood.

[11]  Hong Zhou,et al.  Annexin A2 mediates anti-beta 2 GPI/beta 2 GPI-induced tissue factor expression on monocytes. , 2009, International journal of molecular medicine.

[12]  Hong Zhou,et al.  Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes , 2009 .

[13]  Yin Gao,et al.  TLR4-mediated MyD88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in cortex in mice. , 2009, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[14]  P. Pristovsek,et al.  Essential Roles of Hydrophobic Residues in Both MD-2 and Toll-like Receptor 4 in Activation by Endotoxin* , 2009, Journal of Biological Chemistry.

[15]  R. Beyaert,et al.  A20: Central Gatekeeper in Inflammation and Immunity* , 2009, Journal of Biological Chemistry.

[16]  M. Karin,et al.  Regulation and function of NF-kappaB transcription factors in the immune system. , 2009, Annual review of immunology.

[17]  P. Marynen,et al.  Auto-Ubiquitination-Induced Degradation of MALT1-API2 Prevents BCL10 Destabilization in t(11;18)(q21;q21)-Positive MALT Lymphoma , 2009, PloS one.

[18]  P. Pristovsek,et al.  Taxanes inhibit human TLR4 signaling by binding to MD‐2 , 2008, FEBS letters.

[19]  James P. Snyder,et al.  Paclitaxel Binding to Human and Murine MD-2* , 2008, Journal of Biological Chemistry.

[20]  P. Meroni,et al.  Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome , 2008, Lupus.

[21]  W. Yeh,et al.  LPS/TLR4 signal transduction pathway. , 2008, Cytokine.

[22]  Bettina L. Lee,et al.  Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20 , 2008, The Journal of experimental medicine.

[23]  H. Schultheiss,et al.  Upregulation of tissue factor expression and thrombogenic activity in human aortic smooth muscle cells by irradiation, rapamycin and paclitaxel. , 2008, International immunopharmacology.

[24]  G. Valesini,et al.  Anti-β2-glycoprotein I antibodies induce monocyte release of tumor necrosis factor α and tissue factor by signal transduction pathways involving lipid rafts , 2007 .

[25]  Makiko Kobayashi,et al.  Regulatory Roles for MD-2 and TLR4 in Ligand-Induced Receptor Clustering1 , 2006, The Journal of Immunology.

[26]  Y. Shoenfeld,et al.  International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) , 2006, Journal of thrombosis and haemostasis : JTH.

[27]  C. Coban,et al.  TRAF4 acts as a silencer in TLR‐mediated signaling through the association with TRAF6 and TRIF , 2005, European journal of immunology.

[28]  K. McCrae,et al.  Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies. , 2005, Blood.

[29]  T. Koike,et al.  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. , 2004, International immunology.

[30]  A. Wolberg,et al.  Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. , 2004, Blood.

[31]  Matthew T Wheeler,et al.  The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses , 2004, Nature Immunology.

[32]  P. Cao,et al.  Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling* , 2004, Journal of Biological Chemistry.

[33]  A. Whitehead,et al.  Ubiquitin activated tumor necrosis factor receptor associated factor‐6 (TRAF6) is recycled via deubiquitination , 2003, FEBS letters.

[34]  P. D. de Groot,et al.  Dimers of β2-Glycoprotein I Increase Platelet Deposition to Collagen via Interaction with Phospholipids and the Apolipoprotein E Receptor 2′* , 2003, Journal of Biological Chemistry.

[35]  A. Mantovani,et al.  Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. , 2003, Blood.

[36]  P. Moynagh,et al.  Regulation of Toll-like receptor 4 signalling by A20 zinc finger protein. , 2003, Biochemical and biophysical research communications.

[37]  Sophie Janssens,et al.  Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. , 2003, Molecular cell.

[38]  Charles A. Janeway,et al.  IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling , 2002, Cell.

[39]  J. Morrissey,et al.  Tissue Factor: An Enzyme Cofactor and a True Receptor , 2001, Thrombosis and Haemostasis.

[40]  T. Yasuda,et al.  A specific ligand for beta(2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages. , 2001, Journal of lipid research.

[41]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[42]  K. McCrae,et al.  High Affinity Binding of β2-Glycoprotein I to Human Endothelial Cells Is Mediated by Annexin II* , 2000, The Journal of Biological Chemistry.

[43]  G. Stark,et al.  IRAK-M Is a Novel Member of the Pelle/Interleukin-1 Receptor-associated Kinase (IRAK) Family* , 1999, The Journal of Biological Chemistry.

[44]  R. Beyaert,et al.  The cytokine‐inducible zinc finger protein A20 inhibits IL‐1‐induced NF‐κB activation at the level of TRAF6 , 1999, FEBS letters.

[45]  G. Hughes,et al.  The Role of the Tissue Factor Pathway in the Hypercoagulable State in Patients with the Antiphospholipid Syndrome , 1998, Thrombosis and Haemostasis.

[46]  D. Goeddel,et al.  NF-κB Activation by Interleukin-1 (IL-1) Requires an IL-1 Receptor-associated Protein Kinase Activity (*) , 1995, The Journal of Biological Chemistry.

[47]  R. Brigelius-Flohé,et al.  Interleukin‐1‐induced activation of a protein kinase co‐precipitating with the type I interleukin‐1 receptor in T cells , 1994, European journal of immunology.

[48]  J. Sixma,et al.  Antiphospholipid Antibody Positive Sera Enhance Endothelial Cell Procoagulant Activity – Studies in a Thrombosis Model , 1992, Thrombosis and Haemostasis.

[49]  V. Dixit,et al.  The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. , 1992, The Journal of biological chemistry.

[50]  Hong Zhou,et al.  Involvement of annexin A2 in anti-beta2GPI/beta2GPI-induced tissue factor expression on monocytes. , 2007, Cell research.

[51]  G. Valesini,et al.  Anti-beta2-glycoprotein I antibodies induce monocyte release of tumor necrosis factor alpha and tissue factor by signal transduction pathways involving lipid rafts. , 2007, Arthritis and rheumatism.

[52]  D. Goeddel,et al.  NF-kappa B activation by interleukin-1 (IL-1) requires an IL-1 receptor-associated protein kinase activity. , 1995, The Journal of biological chemistry.