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Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic

Tomoko Ichiki1, Michihisa Jougasaki, Manabu Setoguchi

  • 1Institute for Clinical Research, National Hospital Organization Kagoshima Medical Center, 8-1 Shiroyama-cho, Kagoshima 892-0853, Japan.

American Journal of Physiology. Heart and Circulatory Physiology
|December 7, 2007
PubMed

Insights

Cardiotrophin-1 (CT-1) promotes vascular inflammation by increasing intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression, driving monocyte adhesion and migration in atherosclerosis.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Molecular Medicine

Background:

  • Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) are key mediators of monocyte recruitment in vascular inflammation.
  • Cardiotrophin-1 (CT-1), an IL-6-type cytokine, is present in atherosclerotic plaques, suggesting a potential role in disease pathogenesis.

Purpose of the Study:

  • To investigate whether CT-1 induces monocyte adhesion and migration by upregulating ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs).
  • To elucidate the signaling pathways involved in CT-1-mediated effects on monocyte recruitment.

Main Methods:

  • Immunocytochemistry to assess ICAM-1 and MCP-1 protein levels.
  • Cell adhesion and chemotaxis assays using THP-1 monocytes and HAECs.
  • Western blot analysis for MAP kinase and Akt phosphorylation.
  • RNase protection assay and ELISA for gene and protein expression.
  • Electrophoretic mobility shift assay (EMSA) for NF-kappaB activity.

Main Results:

  • CT-1 significantly increased ICAM-1 and MCP-1 expression and immunoreactivity in HAECs.
  • CT-1 enhanced THP-1 cell adhesion to HAECs and promoted monocyte chemotaxis, effects blocked by anti-ICAM-1 and anti-MCP-1 antibodies.
  • CT-1 induced phosphorylation of ERK1/2, p38 MAP kinase, and Akt, and enhanced NF-kappaB DNA-binding activity.
  • Inhibitors of these signaling pathways (PD-98059, SB-203580, LY-294002, parthenolide) suppressed CT-1-mediated ICAM-1 and MCP-1 upregulation.

Conclusions:

  • CT-1 promotes monocyte adhesion and migration by upregulating ICAM-1 and MCP-1 expression in HAECs.
  • These effects are mediated through activation of ERK1/2, p38 MAP kinase, Akt, and NF-kappaB signaling pathways.
  • CT-1 plays a significant role in the pathophysiology of vascular inflammation and atherosclerosis.

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