Anti-β(2)GPI/β(2)GPI induced TF and TNF-α expression in monocytes involving both TLR4/MyD88 and TLR4/TRIF signaling pathways

Mol Immunol. 2013 Mar;53(3):246-54. doi: 10.1016/j.molimm.2012.08.012. Epub 2012 Sep 8.

Abstract

Our previous study demonstrated that Toll-like receptor 4 (TLR4) could act as a co-receptor with annexin A2 (ANX2) mediating anti-β2-glycoprotein I/β2-glycoprotein I (anti-β(2)GPI/β(2)GPI)-induced tissue factor (TF) expression in human acute monocytic leukemia cell line THP-1. In the current study, we further explored the roles of TLR4 and its adaptors, MyD88 and TRIF, in anti-β(2)GPI/β(2)GPI-induced the activation of human blood monocytes and THP-1 cells and the relationship among TLR4, β(2)GPI and ANX2 in this process. The results showed that treatment of monocytes or THP-1 cells with anti-β(2)GPI/β(2)GPI complex could increase TF, MyD88, TRIF as well as TNF-α (tumor necrosis factor alpha) expression. These effects were blocked by addition of TAK-242, a blocker of signaling transduction mediated by the intracellular domain of TLR4. Moreover, TLR4/β(2)GPI/ANX2 complex could be detected in THP-1 cell lysates. Overall, our results indicate that anti-β(2)GPI/β(2)GPI complex induced TF and TNF-α expression involving both TLR4/MyD88 and TLR4/TRIF signaling pathways and TLR4 and its adaptors might be molecular targets for therapy of antiphospholipid syndrome (APS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Annexin A2 / metabolism
  • Antigen-Antibody Complex / metabolism*
  • Antiphospholipid Syndrome / genetics
  • Antiphospholipid Syndrome / immunology
  • Antiphospholipid Syndrome / metabolism
  • Base Sequence
  • Cell Line
  • DNA Primers / genetics
  • Gene Expression / drug effects
  • Humans
  • In Vitro Techniques
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Thromboplastin / genetics
  • Thromboplastin / metabolism*
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • beta 2-Glycoprotein I / immunology*
  • beta 2-Glycoprotein I / metabolism

Substances

  • ANXA2 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Annexin A2
  • Antigen-Antibody Complex
  • DNA Primers
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • RNA, Messenger
  • Sulfonamides
  • TICAM1 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • beta 2-Glycoprotein I
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • Thromboplastin