Polyphosphate elicits pro-inflammatory responses that are counteracted by activated protein C in both cellular and animal models

Authors

  • J.-S. BAE,

    1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu
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  • W. LEE,

    1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu
    2. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
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  • A. R. REZAIE

    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
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Alireza R. Rezaie, Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
Tel.: +1 314 977 9240; fax: +1 314 977 9205;
E-mail: rezaiear@slu.edu

Abstract

See also Mutch NJ. Polyphosphate scores a hat trick in regulating host defense mechanisms. This issue, pp 1142–4.

Summary.

Background:  Recent results have indicated that polyphosphate, released by activated platelets, can function as a procoagulant to modulate the proteolytic activity of serine proteases of the blood clotting cascade.

Objective:  To determine whether polyphosphate is involved in inducing signal transduction in cellular and animal models.

Methods:  The effect of polyphosphate on human umbilical vein endothelial cells was examined by monitoring cell permeability, apoptosis and activation of NF-κB after treating cells with different concentrations of polyphosphate. Moreover, the expression of cell surface adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and the adhesion of THP-1 cells to polyphosphate-treated cells were monitored using established methods. In the in vivo model, the pro-inflammatory effect of polyphosphate was assessed by monitoring vascular permeability and migration of leukocytes to the peritoneal cavity of mice injected with polyphosphate.

Results:  Polyphosphate, comprised of 45, 65 and 70 phosphate units, enhanced the barrier permeability and apoptosis in cultured endothelial cells and up-regulated the expression of cell adhesion molecules, thereby mediating the adhesion of THP-1 cells to polyphosphate-treated endothelial cells. These effects of polyphosphate were mediated through the activation of NF-κB and could not be recapitulated by another anionic polymer, heparin. Polyphosphate also increased the extravasation of the bovine serum albumin (BSA)-bound Evans blue dye and the migration of leukocytes to the mouse peritoneal cavity, which was prevented when activated protein C (APC) was intravenously (i.v.) injected 2 h before the challenge.

Conclusion:  Polyphosphate, in addition to up-regulation of coagulation, can elicit potent pro-inflammatory responses through the activation of NF-κB, possibly contributing to the pro-inflammatory effect of activated platelets.

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