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Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine

Joseph J Boyle1, Peter L Weissberg, Martin R Bennett

  • 1Unit of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK. joseph.boyle@ic.ac.uk

Arteriosclerosis, Thrombosis, and Vascular Biology
|July 19, 2003
PubMed
Abstract

Insights

Tumor necrosis factor-alpha (TNF-alpha) promotes vascular smooth muscle cell (VSMC) apoptosis, a key factor in plaque rupture. This occurs via direct and autocrine pathways, involving nitric oxide (NO) and TNF-alpha receptor interactions.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Cellular Pathology

Background:

  • Human macrophages induce vascular smooth muscle cell (VSMC) apoptosis via cell-cell contact, Fas-L, and nitric oxide (NO).
  • This process contributes to atherosclerotic plaque rupture.

Purpose of the Study:

  • To investigate the additional role of tumor necrosis factor-alpha (TNF-alpha) in macrophage-induced VSMC apoptosis.

Main Methods:

  • Direct co-culture of macrophages and VSMCs.
  • Use of antagonistic antibodies against TNF-receptor 1 (TNF-R1).
  • Assessment of TNF-R1 expression on monocytes and VSMCs, and TNF-alpha on macrophages.

Main Results:

  • Anti-TNF-R1 antibodies inhibited VSMC apoptosis.
  • Both monocytes and VSMCs expressed TNF-R1, contributing to apoptosis.
  • Nitric oxide (NO) donors upregulated VSMC TNF-R1, sensitizing cells to TNF-alpha.
  • TNF-alpha and NO synergistically induced VSMC apoptosis.
  • Anti-TNF-R1 antibodies reduced macrophage-derived Fas-L expression and NO secretion.

Conclusions:

  • TNF-alpha significantly contributes to macrophage-induced VSMC apoptosis.
  • This occurs through both autocrine (on macrophages) and direct (on VSMCs) pathways.
  • TNF-alpha and NO signaling pathways are intertwined in promoting VSMC apoptosis.

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