Suppressive effects of collismycin C on polyphosphate-mediated vascular inflammatory responses

Human endothelial cells-derived polyphosphate (PolyP) is one of the pro-inflammatory mediators as suggested by the previous reports. 2,2'-bipyridine containing natural products are generally accepted to have antimicrobial, cytotoxic and anti-inflammatory properties. This study was undertaken to investigate whether a 2,2'-bipyridine containing natural product, collismycins C, can modulate PolyP-mediated inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. After HUVECs or mice were activated with PolyP, cells or mice were post-treated with collismycins C. The anti-inflammatory activities of collismycins C were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in PolyP-activated HUVECs and mice. In addition, the beneficial effects of collismycins C on survival rate in PolyP-injected mice. Collismycins C inhibits PolyP-mediated barrier disruption, the expressions of cell adhesion molecules, and leukocyte to HUVEC adhesion/migration. Interestingly, PolyP-induced NF-kappa B activation and the productions of TNF-alpha and IL-6 were inhibited by collismycins C in HUVECs. These anti-inflammatory functions of collismycins C were confirmed in PolyP injected mice. In conclusion, based on the anti-inflammatory effects of collismycins C in PolyP-mediated septic response, collismycins C have therapeutic potential for various systemic inflammatory diseases.