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

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.

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

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.

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.

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.