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Activation of mTOR is involved in anti-β2GPI/β2GPI-induced expression of tissue factor and IL-8 in monocytes

Longfei Xia1, Hong Zhou2, Ting Wang3

  • 1Jiangsu Key Laboratory of Medicine Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Department of Laboratory Medicine, Fourth Hospital of Hebei Medical University, Shi Jiazhuang, Hebei 050000, PR China.

Thrombosis Research
|July 23, 2017
PubMed

Insights

The mammalian target of rapamycin (mTOR) pathway is implicated in antiphospholipid syndrome (APS). Inhibiting mTOR reduces tissue factor and IL-8 expression in monocytes, suggesting a therapeutic target for APS-related thrombosis and inflammation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pathophysiology

Background:

  • Antiphospholipid syndrome (APS) is linked to chronic vascular lesions and a prothrombotic state, partly due to antiphospholipid antibodies (aPL) activating endothelial cells and monocytes.
  • Previous studies linked mammalian target of rapamycin (mTOR) pathway activation in endothelial cells to APS-related vascular lesions.
  • The specific role of mTOR in the pathogenic mechanisms of APS, particularly in monocyte activation, remained largely unexplored.

Purpose of the Study:

  • To investigate the involvement of mTOR in the expression of tissue factor (TF) and interleukin-8 (IL-8/CXCL8) in monocytes induced by anti-β2GPI/β2GPI complexes.
  • To explore the intricate relationship among Toll-like receptor 4 (TLR4), mTOR, mitogen-activated protein kinases (MAPKs), and nuclear factor-kappa B (NF-κB) in this process.

Main Methods:

  • Treatment of THP-1 cells and primary monocytes with anti-β2GPI/β2GPI or APS-IgG/β2GPI complexes.
  • Assessment of mTOR activation, TF, and IL-8 expression.
  • Utilized mTOR inhibitor rapamycin, specific MAPK inhibitors (p38, ERK1/2, JNK), and a TLR4 inhibitor (TAK-242).

Main Results:

  • Anti-β2GPI/β2GPI or APS-IgG/β2GPI complex treatment significantly activated mTOR and increased TF and IL-8 expression in monocytes.
  • Rapamycin treatment attenuated the elevated TF and IL-8 expression and decreased the phosphorylation of p38, ERK1/2, and NF-κB p65.
  • Inhibition of p38 or ERK, but not JNK or NF-κB, reduced mTOR phosphorylation; TLR4 inhibition also affected mTOR activation.

Conclusions:

  • mTOR plays a crucial role in regulating the expression of TF and IL-8 in monocytes induced by anti-β2GPI/β2GPI complexes.
  • The findings elucidate a signaling cascade involving TLR4, MAPKs, and mTOR in APS pathogenesis.
  • Inhibition of the mTOR pathway presents a potential therapeutic strategy for preventing and treating aPL-mediated thrombosis and inflammation in APS patients.
Keywords:
Anti-β(2)-glycoprotein I antibodiesInterleukin-8Tissue factormTORβ(2)-glycoprotein I

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