Lysophosphatidic Acid Activates Nuclear Factor Kappa B and Induces Proinflammatory Gene Expression in Endothelial Cells

Alois Palmetshofer; Simon C. Robson; Volker Nehls

doi:10.1055/s-0037-1614867

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(05): 1532-1537
DOI: 10.1055/s-0037-1614867

Rapid Communications

Schattauer GmbH

Lysophosphatidic Acid Activates Nuclear Factor Kappa B and Induces Proinflammatory Gene Expression in Endothelial Cells

Alois Palmetshofer

¹From the Institut für Klinische Biochemie und Pathobiochemie, Medizinische Kliniken Würzburg, Germany

,

Simon C. Robson

²Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, USA

,

Volker Nehls

¹From the Institut für Klinische Biochemie und Pathobiochemie, Medizinische Kliniken Würzburg, Germany

› Author Affiliations

Abstract

Summary

The cellular phospholipid, lysophosphatidic acid (LPA), released by activated platelets and fibroblasts or, at high levels, from ovarian and cervical carcinomas is a powerful serum mitogen that may modulate several signaling pathways in endothelial cells (EC). Hence, LPA could function in a paracrine manner during EC-platelet interactions at sites of vascular injury.

Here, we demonstrate activation of the transcription factor nuclear factor kappa B (NF-κB) in EC following exposure to LPA. EC activation was further characterized by increased levels of mRNA transcripts encoding E-selectin, Intercellular Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoattractant Protein-1. These effects were inhibited by preincubating EC either in the presence of mepacrine (to block phospholipase A₂) or of pertussis toxin (to increase ADP-ribosylation of G_i proteins). No inhibition was observed in the presence of putative LPA receptor antagonists suramin or thrombospondin.

LPA induces a proinflammatory activation of endothelial cells that (i) involves G_i proteins; (ii) depends on phospholipase A₂ activity; (iii) is associated with the activation of NF-κB and (iv) results in increased expression of proinflammatory genes. We propose that LPA release by activated platelets may directly modulate vascular inflammatory responses.

Abbreviations: EC, endothelial cells; LPA, lysophosphatidic acid; NF-κB, nuclear factor kappa B; PA, phosphatidic acid; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1, ICAM-1, intercellular adhesion molecule-1, vascular adhesion molecule-1; GAPDH, glycerol aldehyde phosphate dehydrogenase; MAPK, mitogen activated kinase, MEK, MAPK kinase, PAEC, porcine aortic EC.

Keywords

Lysophosphatidic acid - nuclear factor kappa B - transcription factor - inflammation - endothelial cells - platelets - gene expression

Full Text

References

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