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Activation of toll-like receptor 4 modulates vascular endothelial growth factor synthesis through prostacyclin-IP

Dae-Weon Park1, Kheewoong Baek, Jin-Gu Lee

  • 1Aging-associated Vascular Disease Research Center, Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea.

Biochemical and Biophysical Research Communications
|September 11, 2007
PubMed

Insights

Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) stimulates prostaglandin I2 (PGI2) production and vascular endothelial growth factor (VEGF) release in macrophages, mediated by the Akt pathway and IP receptor.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS) is a key inflammatory pathway.
  • Cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) are involved in inflammatory responses.
  • Vascular Endothelial Growth Factor (VEGF) is a critical regulator of angiogenesis.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking TLR4 activation to VEGF production in macrophages.
  • To investigate the role of COX-2, PGI2, and specific receptors in this process.
  • To determine the involvement of the Akt signaling pathway.

Main Methods:

  • Macrophage stimulation with LPS and specific receptor agonists.
  • Inhibition of COX-2 activity using NS-398.
  • Gene silencing of IP receptor using micro interfering RNA.
  • Assessment of Akt phosphorylation.
  • Measurement of PGI2 and VEGF production.

Main Results:

  • LPS-induced COX-2 expression and PGI2 formation were suppressed by a COX-2 inhibitor.
  • LPS stimulation led to increased VEGF production, which was blocked by inhibiting IP receptor or Akt phosphorylation.
  • Iloprost, a PGI2 analogue, induced VEGF production via the IP receptor.
  • Akt phosphorylation was transiently induced by LPS and essential for VEGF and COX-2 expression.

Conclusions:

  • TLR4 engagement by LPS induces PGI2 production through the Akt pathway.
  • This PGI2, acting via the IP receptor, subsequently generates VEGF.
  • The TLR4-LPS-Akt-PGI2-IP receptor-VEGF axis represents a novel signaling pathway in macrophages.

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