TRAIL promotes caspase-dependent pro-inflammatory responses via PKCδ activation by vascular smooth muscle cells

Area of Science:

• Immunology
• Molecular Biology
• Cardiovascular Research

Background:

• Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells but can promote inflammation in normal cells.
• The precise mechanisms of TRAIL's involvement in vascular disorders remain unclear.
• Nuclear factor-κB (NF-κB) signaling is implicated in inflammatory vascular responses.

Purpose of the Study:

• To elucidate the role of TRAIL in inflammatory vascular responses.
• To identify molecular mechanisms underlying TRAIL-mediated vascular inflammation.
• To explore potential therapeutic targets for restenosis and atherosclerosis.

Main Methods:

• Primary human vascular smooth muscle cells were treated with TRAIL.
• Expression of intercellular adhesion molecule-1 (ICAM-1) was analyzed.
• Protein kinase C delta (PKCδ) activation and cleavage were investigated using mutants.
• NF-κB activation was assessed.
• In vivo studies examined post-traumatic vascular remodeling.

Main Results:

• TRAIL treatment upregulated ICAM-1 expression in vascular smooth muscle cells.
• This upregulation was mediated by PKCδ and NF-κB activation.
• PKCδ activation resulted from caspase-dependent proteolysis.
• PKCδ demonstrated a protective role in vivo during vascular remodeling.

Conclusions:

• The TRAIL/TRAIL receptor system plays a significant role in inflammatory vascular disease pathogenesis.
• TRAIL transduces pro-inflammatory signals through caspase-mediated PKCδ cleavage and NF-κB activation.
• This pathway offers potential targets for preventing and treating vascular conditions like restenosis and atherosclerosis.