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CD40-40L signaling in vascular inflammation

Subrata Chakrabarti1, Price Blair1, Jane E Freedman1

  • 1Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.

The Journal of Biological Chemistry
|April 27, 2007
PubMed

Insights

CD40L binding to CD40 triggers inflammatory responses in endothelial cells via a redox-sensitive pathway involving Akt and p38 MAPK. This signaling cascade activates NF-kappaB, increasing CD40L and MCP1, potentially promoting atherothrombosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Signaling
  • Immunology

Background:

  • CD40 ligation in the vasculature can promote inflammation, plaque instability, and thrombosis.
  • The precise redox-sensitive signaling mechanisms linking CD40-CD40L interactions to inflammatory mediator release remain incompletely understood.
  • Previous work indicated CD40-CD40L interactions modulate reactive oxygen species (ROS) release.

Purpose of the Study:

  • To elucidate the signaling pathway by which CD40L binding to CD40 mediates inflammatory secretion in endothelial cells.
  • To investigate the role of redox sensitivity in CD40L-induced inflammatory responses.
  • To identify key kinases and transcription factors involved in CD40L-mediated endothelial cell activation.

Main Methods:

  • Endothelial cells were treated with recombinant CD40L or adenoviral vectors.
  • Pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) were used.
  • Adenovirus-mediated gene transfer was employed to inactivate Akt and p38 MAPK.
  • Confocal microscopy assessed nuclear translocation of NF-kappaB.
  • Intracellular CD40L and MCP1 levels were quantified.

Main Results:

  • CD40L dose-dependently induced intracellular CD40L and MCP1 release in endothelial cells in a redox-sensitive manner.
  • Inhibition of PI3K and p38 MAPK, or inactivation of Akt and p38 MAPK, blocked CD40L effects.
  • Akt mediated CD40L-induced CD40L synthesis and MCP1 release via NF-kappaB activation in a redox-sensitive pathway.
  • CD40L stimulation promoted NF-kappaB nuclear translocation, an effect augmented by Akt and inhibited by Akt inactivation.

Conclusions:

  • Redox-sensitive CD40-CD40L interactions activate Akt and p38 MAPK, leading to NF-kappaB stimulation.
  • This pathway enhances the synthesis of CD40L and MCP1 in endothelial cells.
  • Elevated CD40L and MCP1 may contribute to atherothrombosis by increasing the adherence of CD40-positive cells like monocytes and platelets to the vessel wall.

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